Periodontology 2000 - 2023 - Bobetsis - Periodontal Diseases and Adverse Pregnancy Outcomes Present and Future

Received: 11 October 2022 | Revised: 2 February 2023 | Accepted: 11 March 2023
DOI: 10.1111/prd.12486
REVIEW ARTICLE
Periodontal diseases and adverse pregnancy outcomes. Present

and future
Yiorgos A. Bobetsis1 | Mark Ide2 | Mervi Gürsoy3 | Phoebus N. Madianos1

1
Department of Periodontology, National and Kapodistrian University of Athens, Athens, Greece
2
Faculty of Dentistry Oral and Craniofacial Sciences, King's College London, London, UK
3
Department of Periodontology, University of Turku, Turku, Finland
Correspondence
Phoebus N. Madianos, Department of Periodontology, National and Kapodistrian University of Athens, 2 Thivon str. Goudi, 11527 Athens, Greece.
Email: pmadian@dent.uoa.gr
1 | I NTRO D U C TI O N several methodologic limitations remain a significant drawback for

this set of investigations, and therefore safe conclusions are not al-
Despite the advances in prenatal care and increased public aware- ways easy to draw. The goal of this article is to briefly describe the
ness, recent data from the World Health Organization suggest that established knowledge and give emphasis to the current literature
the prevalence of adverse pregnancy outcomes remains high. At (2018 to March 2022). In addition, owing to the main theme of this
a global scale, preterm birth appears to affect around 10.6% of all Periodontology 2000 volume, special reference will be made regard-
pregnancies, and low birth weight 23.4% and preeclamsia 4.6%.1–3 ing the results from European studies on periodontal diseases and
The significance of these numbers lies in the fact that obstetric adverse pregnancy outcomes. Finally, future directions and research
complications represent a significant cause of maternal and fetal/ guidelines will be proposed in order to move on to the next level
4
neonatal morbidity and mortality. Moreover, preterm and low birth of evidence that will help connect the theoretical knowledge with
weight infants who survive the neonatal period face a higher risk meaningful clinical interventions that will benefit our pregnant pa-
of multiple lifelong challenges, such as respiratory distress, impaired tients and their offspring.
motor skills, cognitive and intellectual impairment, learning difficul-
ties, and cardiovascular and metabolic disorders.5 Therefore, ad-
verse pregnancy outcomes are an important public health problem 2 | O B S E RVATI O N A L S T U D I E S
with significant social and financial implications.
Although several risk factors have been recognized, in more than More than 120 observational studies, including cohort studies,
6
50% of cases the etiologic factors of prematurity are unknown. case-control, and cross-sectional studies, have been conducted
Intrauterine and other infections account for 75% of preterm birth worldwide with a clear preference to explore the association of
and/or low birth weight, and subclinical infections are beginning to periodontal diseases with preterm birth, low birth weight, and, to a
be considered as an important cause of very premature birth.7 Oral lesser extent, preeclampsia. Hence, the association of periodontal
infections might also be accountable for pregnancy complications, diseases with miscarriage, gestational diabetes mellitus, and other
since commensal bacterial species of the oral cavity colonize the fe- less frequent adverse pregnancy outcomes has been investigated
toplacental unit of women with full-term gestation and with adverse only occasionally. Findings reported from these observational
pregnancy outcomes.8 studies are contradictory, and thus do not lead to solid evidence
Therefore, for more than two decades, the possible association of this relationship.9,14,15 Even the large-sample prospective studies
between periodontal diseases and adverse pregnancy outcomes has with adjusted data that have been thoroughly discussed in a recent
been extensively evaluated. Observational, intervention and mech- review5 and offer the best available evidence among observational
anistic studies have offered valuable information on this topic and studies do not point toward a clear direction regarding this
5,9–13
have been presented in previous thorough reviews. However, association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Periodontology 2000 published by John Wiley & Sons Ltd.
Periodontology 2000. 2023;00:1–28. wileyonlinelibrary.com/journal/prd | 1

|
16000757, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/prd.12486 by CAPES, Wiley Online Library on [28/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2 BOBETSIS et al.
This heterogeneity among the results could be explained by the Specifically, the relative risk for preterm birth was 1.6 (95% confi-
significant inconsistency in the methodology used. Differences in dence interval: 1.3-2.0), for low birth weight the relative risk was 1.7
case definition is probably the weakest point of this set of studies, (95% confidence interval: 1.3-2.1), for preterm low birth weight the
despite the fact that the American Academy of Periodontology and relative risk was 3.4 (95% confidence interval: 1.3-8.8), and for pre-
United States Centers for Disease Control and Prevention16 and the eclampsia the odds ratio was 2.2 (95% confidence interval: 1.4-3.4).
17
European Federation of Periodontology have developed standard- Based on these figures, it was estimated that periodontal diseases
ized clinical case definitions for population-based trials on periodon- contributed 5%-38% of the global risk for preterm birth, 6%-41%
titis. It is clear that allocation of pregnant women in the disease or for low birth weight, and 10%-55% for preeclampsia. However,
nondisease group based on self-reports or the use of partial or full Daalderop et al acknowledged that the meta-analyses may have
mouth clinical measurements with different cut-off points of disease overestimated the strength of the associations under study since
could greatly affect the outcome of the epidemiologic studies.18 several primary studies did not adjust for confounding. Finally, a re-
A second important reason for the variability among the obser- cent systematic review that included six cohort studies with a total
vational studies is the inadequate adjustment for confounding fac- of 2724 pregnant women evaluated the association of periodonti-
tors. The age of the pregnant woman, race, socioeconomic status, tis with preeclampsia. 22 All but one study confirmed a significant
education, smoking, drug use, parity, prenatal care, history of preg- association.
nancy complications, genitourinary infections, body mass index, oral During the last 5 years, 15 observational studies looking into
health, and diabetes mellitus are some of the risk factors that may af- the association of periodontal diseases with adverse pregnancy
fect periodontal health and/or pregnancy outcomes. Unfortunately, outcomes have been identified in PubMed and the Cochrane
a significant volume of the available evidence has been generated by Library. Four studies are cohorts, 23–26 10 are case-controls or cross-
studies with poor and inconsistent adjustment of these confounding sectional, 27–36 and one is a secondary analysis of a multicenter cross-
variables. sectional study with a nested case-control.37 As shown in Table 1,
Large differences in the size of the study populations could also despite the recommendations for a more uniform methodology,
contribute to the variability among the observational studies. Results there is a diversity in the sample size of the populations enrolled, in
derived from studies with a very small number of participants may the type of periodontal recording, and in the case definition that is
be underpowered and, therefore, should be interpreted with cau- still obvious among studies.
tion. Finally, since the incidence of adverse pregnancy outcomes and An attempt to convert the different definitions of periodontitis
the prevalence of periodontal diseases vary among different races, employed using the new 2017 classification system38 turned out
conclusions from reports targeting specific ethnic groups should not to be very challenging and with uncertain results. From all studies
be generalized.19 published since 2018, nine23,26–28,30–33,36 defined periodontitis using
Despite the methodological inconsistencies and the contradic- clinical attachment loss measurements, albeit with different cutoff
tory results, numerous systematic reviews and meta-analyses have points. However, only one cohort adopted the new classification
tried to assess whether an association between periodontal diseases system incorporating both the stage and grade of periodontitis. In
and adverse pregnancy outcomes exists and, if present, evaluate its that study, cases had stage II grade B periodontitis. 23 In two30,36
magnitude. In 2013, a thorough systematic review9 published as out of the three studies that took interproximal clinical attachment
part of the proceedings of a workshop on periodontitis and sys- loss measurements, the severity of periodontitis resembled that of
temic diseases that was held jointly by the European Federation of stages II and III; and in the third study, stage I periodontitis was also
Periodontology and the American Academy of Periodontology, con- included.32 For the remaining studies, the lack of information regard-
cluded that preterm birth, low birth weight, and preeclampsia are as- ing interproximal clinical attachment loss measurements, bone loss
sociated with maternal exposure to periodontal diseases. However, levels, and number of missing teeth prevented the adoption of the
the strength of the observed associations is modest and seems to new classification system. As already discussed, it is possible that
vary according to the population studied, the means of periodontal variations in patient allocation in the case or control groups could
9,14
assessment, and the periodontal diseases classification employed. have largely contributed to the significant heterogeneity in the re-
Interestingly, 5 years later, in an umbrella review of systematic sults observed.
reviews with or without meta-analysis, Vivares-Builes et al20 found
that from the 19 studies included, seven showed a “moderate pos-
itive” association; the remaining 12 systematic reviews demon- 2.1 | Association with preterm birth
strated a “high positive” association between periodontal diseases
and preterm birth, low birth weight, and preeclampsia. Similarly, the From the three cohort studies23–25 evaluating the association of
same year in another systematic overview of 23 systematic reviews, periodontal diseases with preterm birth, only one found a positive
21
Daalderop et al demonstrated that, among the systematic reviews association. 25 This was a nationwide population-based cohort of
with the lowest risk of bias, periodontal diseases were, again, pos- 1 757 774 participants from Taiwan. In that study, the presence and
itively associated with preterm birth, low birth weight, preterm severity of periodontal diseases was defined by the treatment codes
low birth weight, and preeclampsia, albeit with different strength. derived from the periodontal treatment they had received within
TA B L E 1 Observational studies over the last 5 years that examined the association between periodontal disease (defined with clinical parameters) and adverse pregnancy outcomes
Characteristics of
Reference Location Study type population Sample size Periodontitis definition Type of recording Main findings
23
BOBETSIS et al.
Caneiro et al Spain Cohort Evaluation at 1st, 2nd, 158 Interdental clinical attachment Full mouth periodontal Periodontitis stage II, grade
and 3rd trimesters loss at ≥2 nonadjacent teeth evaluation B was not associated with
or buccal or oral clinical preterm birth
attachment loss ≥3 mm with
probing depth ≥3 mm at ≥2
teeth
Erchick et al24 Nepal Community-based <26 wk of gestation 1474 Gingival inflammation, defined Full periodontal In the final adjusted model,
prospective cohort as bleeding on probing ≥10%, recording increasing extent of
study stratified by bleeding on probing gingival inflammation
<30% and bleeding on probing was associated with a
≥30%. Mild periodontitis was nonsignificant increase
defined as ≥2 interproximal in risk of preterm birth
sites with probing pocket (bleeding on probing
depth ≥4 mm (not on the same ≥30% vs no bleeding on
tooth) or one site with probing probing: adjusted relative
pocket depth ≥5 mm. Moderate risk 1.37; 95% confidence
periodontitis was defined as ≥2 interval: 0.81‑2.32). In
interproximal sites with probing the final adjusted model
pocket depth ≥5 mm (not on the stratified by trimester,
same tooth) there was a positive
relationship between
gingival inflammation and
risk of preterm birth among
women in the first trimester
(bleeding on probing
≥30% vs no bleeding on
probing: adjusted relative
risk 2.57; 95% confidence
interval: 1.11‑5.95), but
not among women in
their second trimester
(bleeding on probing ≥30%
vs no bleeding on probing:
adjusted relative risk 1.05;
95% confidence interval:
0.52‑2.11).
Mild periodontitis was not
associated with preterm
birth
| 3
(Continues)
4
TA B L E 1 (Continued)
|
Characteristics of
25
Lee et al Taiwan Nationwide population- Periodontal disease 1 757 774 Used ICD-9-CM and periodontal Not available Advanced periodontal disease
based cohort evaluated during a disease treatment codes to group had adjusted odds
2-y period prior for define periodontal disease ratio 1.09 (95% confidence
giving birth severity and stratified into interval: 1.07‑1.11) for
mild periodontal disease and preterm birth, the mild
advanced periodontal disease periodontal disease group
groups had adjusted odds ratio
1.05 (95% confidence
interval: 1.04‑0.06),
whereas the no periodontal
disease group had adjusted
odds ratio 1. Increased
periodontal disease severity
was related to higher risk of
preterm birth
Ye et al26 China Prospective clinical trial Periodontal evaluation 186 Gingival redness with ≥4 teeth Full mouth periodontal Periodontal disease was not
during 2nd trimester exhibiting ≥1 site of probing recording associated with preterm
pocket depth ≥4 mm and/or low birth weight
bleeding on probing at >25%
of sites. Within the periodontal
disease group, subjects who
had clinical attachment loss
>0 were diagnosed with
periodontitis and those with
clinical attachment loss = 0 were
diagnosed as gingivitis. Subjects
who did not fulfill these criteria
were diagnosed as clinically
healthy
Fogacci et a27 Brazil Case-control 28‑32 wk of gestation 287 Periodontitis severity and extent Full mouth periodontal Periodontitis was not
was evaluated in relation recording associated with preterm
with clinical attachment loss. low birth weight
Severity levels 2, 3, and 4 were
designated, respectively, when
the mean clinical attachment
loss was higher than 2, 3, or
4, and extent levels 2, 3, and
4 represent the percentage of
sites with clinical attachment
loss ≥2, ≥3, or ≥4, respectively
BOBETSIS et al.
Characteristics of
BOBETSIS et al.
Silveira da Mota Brazil Case-control Postpartum women 444 Gingivitis: probing pocket depth Periodontal recordings Periodontal disease was not
Krüger et al28 ≥4 mm and clinical attachment in 6 sites per tooth associated with preterm
loss ≥3 mm in the same site of 14 teeth birth or preterm low birth
in ≤1 tooth, with gingival weight
inflammation sign (redness,
swelling and/or bleeding
on probing). Localized
periodontitis: probing pocket
depth ≥4 mm and clinical
attachment loss ≥3 mm in
the same site in 2 or 3 teeth,
with bleeding on probing.
Generalized periodontitis:
probing pocket depth ≥4 mm
and clinical attachment loss
≥3 mm in the same site in ≥4
teeth, with bleeding on probing
Lafaurie et al29 Colombia Case-control Postpartum women 535 Patients were classified according Community periodontal The presence of probing
to probing pocket depth (code index pocket depth was
3: probing pocket depth 4-5 mm; associated with preterm
or code 4: probing pocket depth birth (adjusted odds ratio
>5 mm) in ≥1 sextant of the 2.04; 95% confidence
mouth interval: 1.10‑3.64), low
birth weight (adjusted odds
ratio 2.52; 95% confidence
interval: 1.36‑4.70),
preterm low birth weight
(adjusted odds ratio 2.08;
1.18‑3.31), premature
rupture of membranes
1.17‑3.56), preeclampsia
1.88‑17.4)
| 5
(Continues)
6
|
Characteristics of
Gomes-Filho Brazil Case-control Postpartum women 732 Mild periodontitis: ≥2 interproximal Full mouth periodontal In the group with hemoglobin
et al30 sites with clinical attachment recording A1c levels <5.6%, a
loss ≥3 mm (not in the same statistically significant
tooth) and ≥2 interproximal relationship existed
sites with probing pocket depth between periodontitis
≥4 mm (not in the same tooth) or and low birth weight
1 site with probing pocket depth (adjusted odds ratio 1.55;
≥5 mm. 95% confidence interval:
No periodontitis: No evidence 1.04‑2.31). In the group
of mild, moderate, or severe with higher hemoglobin
periodontitis A1c levels but still within
the normal range (≥5.6%
and <6.5%), the findings
showed no association
between periodontitis and
low birth weight
Márquez-Corona Mexico Pilot case-control Women receiving 111 The severity of periodontal Not determined Significant differences were
et al31 prenatal care disease was graded as follows. but probably observed with gingivitis
Absent: probing pocket depth full periodontal (P < 0.01) and periodontitis
<3 mm and clinical attachment recording at 6 sites (P < 0.001). When the
loss <2 mm. Mild: probing per tooth severity of gingivitis or
pocket depth ≥3 mm or clinical periodontitis increased,
attachment loss ≥2 mm. the percentage of cases
Moderate: ≥2 sites with probing of preterm birth increased
pocket depth ≥5 mm and ≥2 (P < 0.01). The average
sites with clinical attachment number of teeth lost was
loss ≥2 mm. Severe: ≥4 sites higher among the cases
with probing pocket depth than among the controls
≥5 mm and ≥4 sites with clinical (1.33 ± 1.89 vs 0.81 ± 1.82,
attachment loss ≥2 mm P < 0.05)
Uwambaye et al32 Rwanda Multicenter Postpartum women 555 Periodontitis: probing pocket Full mouth periodontal A statistically significant
retrospective depth >3 mm on either maxilla recording association was found
case-control or mandible or both and between periodontitis and
presence of interdental clinical preterm birth (odds ratio:
attachment loss ≥2 mm on 6.36; 95% confidence
either maxilla, mandible, or interval: 3.9‑10.4)
both and buccal or oral clinical
attachment loss ≥3 mm
BOBETSIS et al.
Characteristics of
33
BOBETSIS et al.
Micu et al Romania Cross-sectional Postpartum women 194 Periodontal disease was defined Full mouth periodontal Multivariate analysis
case-control as the presence of ≥4 teeth recording highlighted that the
showing ≥1 site with probing presence of postpartum
pocket depth ≥4 mm and with maternal periodontitis
clinical attachment loss ≥3 mm and its severity remained
at the same site independent risk factors
of preterm birth in the
presence of antepartum
smoking habit and route
of delivery; adjusted odds
ratio 2.26 (95% confidence
interval: 1.06‑4.82) and
odds ratio 3.46 (95%
confidence interval:
1.08‑11.15), respectively
Tedesco et al37 Brazil Secondary analysis of a Included women 2682 Yes/no based on participant's Self-reported infectious 9.6% of women with preterm
multicenter cross- with spontaneous report condition birth and maternal infection
sectional study with preterm birth were classified as having
a nested case-control and/or preterm periodontal infection only
component premature rupture
of membranes
Gesase et al34 Tanzania Cross-sectional Postpartum 1117 A score of 0 meant no periodontal Community periodontal Periodontal disease was
disease, 1‑2 gingivitis, and 3‑4 index significantly associated with
periodontitis higher odds of preeclampsia
2.20‑7.90), low birth weight
1.34‑4.33), and preterm
birth (adjusted odds ratio
2.32; 95% confidence
interval: 1.33‑4.27). No
significant association
between periodontal disease
and preterm premature
rupture of membranes
(adjusted odds ratios 1.83;
0.75‑4.21) and eclampsia
(3.71; 95% confidence
interval: 0.80‑17.13)
| 7
(Continues)
| 8
Characteristics of
Kopycka- United States Retrospective from 316 956 Yes/no based on participant's Questionnaire: “Did you Women who reported
Kedzierawski database answer to questionnaire have any problems periodontal disease were
et al35 with your gums at less likely to have preterm
any time during birth (odds ratio 0.94;
pregnancy, for 95% confidence interval:
example, swollen or 0.91‑0.97), and deliver
bleeding gums?” babies with low birth
weight (odds ratio 0.93;
0.90‑0.97)
Mahapatra et al36 India Cross-sectional 13-32 wk of gestation 156 Mild periodontitis: ≥2 interproximal Full mouth periodontal No association of probing
sites with clinical attachment recording pocket depth and clinical
loss ≥3 mm or ≥2 interproximal attachment loss with low
sites with probing pocket birth weight. Bleeding on
depth ≥4 mm (not on the same probing and gingival index
tooth) or ≥1 site with probing were significantly higher
pocket depth ≥5 mm. Moderate in women with low birth
periodontitis: ≥2 interproximal weight
sites with clinical attachment
loss ≥4 mm or ≥2 interproximal
sites with probing pocket
depth ≥5 mm (not on the same
tooth). Severe periodontitis: ≥2
interproximal sites with clinical
attachment loss ≥6 mm and ≥1
interproximal site with probing
pocket depth ≥5 mm (not on
the same tooth). Gingivitis:
presence of inflammation and
bleeding on probing in patients
not diagnosed with periodontitis
BOBETSIS et al.
|
BOBETSIS et al. 9
2 years prior to the day of delivery. After adjusting for confound- 2.08 (95% confidence interval: 1.18‑3.3). The case-control by
ing factors, increased disease severity was related to higher risk of Silveira da Mota Krüger et al28 reported no association. Similarly,
preterm birth. Specifically, the advanced periodontitis group had an Fogacci et al, 27 in another case-control study held in Brazil that in-
adjusted odds ratio of 1.09 (95% confidence interval: 1.07‑1.11) for cluded 287 women, also did not find a positive association between
preterm birth, and the mild periodontitis group had an adjusted odds periodontitis and preterm low birth weight. Finally, a very recent
ratio 1.05 (95% confidence interval: 1.04‑1.06). prospective clinical trial from China reporting data from 186 preg-
From the five case-control studies, 28,29,31–33 four29,31–33 showed nant women failed again to find an association with preterm low
a positive association between periodontitis and preterm birth, with birth weight. 26
29
odds ratio ranging from 2.04 (95% confidence interval: 1.1‑3.6) to
32
6.36 (95% confidence interval: 3.9‑10.4). The highest odds ratio
derived from a multicenter retrospective case-control study in 2.4 | Association with preeclampsia
Rwanda involving 555 postpartum women.
Finally, from the four cross-sectional studies,34–37 only one34 Both investigations evaluating the association of periodontal dis-
demonstrated a positive association between gingivitis or periodon- eases with preeclampsia found a positive association. In the stud-
titis and preterm birth. This study involved 1117 postpartum women ies by Gesase et al34 and Lafaurie et al, 29 the adjusted odds ratio of
from northern Tanzania, where periodontal diseases were defined preeclampsia in pregnant women with periodontal diseases was 4.12
using the community periodontal index. Periodontal diseases were (95% confidence interval: 2.2‑7.9) and 5.73 (95% confidence interval:
significantly associated with higher odds of preterm birth after ad- 1.88‑17.4), respectively.
justing for confounders (adjusted odds ratio 2.32; 95% confidence
interval: 1.33‑4.27).34
3 | R EG I O N A L VA R I ATI O N S I N
TH E I N C I D E N C E R ATE S O F A DV E R S E
2.2 | Association with low birth weight PR EG N A N C Y O U TCO M E S
From the five studies29,30,34–36 evaluating the association of peri- Based on a recent systematic review on global, regional, and na-
29,30,34
odontal diseases with low birth weight, three were positive. tional estimates of levels of preterm birth, the global incidence of
The reports by Gesase et al34 and Lafaurie et al29 found that peri- preterm birth in 2014 was around 10.6% of all births, representing
odontal diseases were significantly associated with higher odds of 14.8 million births, with regional disparities. The lowest incidence
low birth weight (adjusted odds ratio 2.41; 95% confidence interval: was in Europe (8.7%) and the highest in North Africa (13.4%).1
1.34‑4.33;34 and adjusted odds ratio 2.52; 95% confidence interval: Noteworthy is that the highest proportions of global preterm births
1.36‑4.7029). 29,34 In contrast, the study by Kopycka-Kedzierawski were in Asia (52.9%) and sub-Saharan Africa (28.2%), whereas the
et al35 did not show such an association. In a Brazilian case-control lowest rates occurred in Oceania (0.4%), North America (3.3%), and
study including 732 postpartum women, the group with hemo- Europe (4.7%). Moreover, Zeitlin et al39 investigated the rates of pre-
globin A1c levels below 5.6% demonstrated, after adjustment for term births across 19 European countries between 1996 and 2008.
confounding factors, a statistically significant relationship between Overall, in 2008, preterm birth rates for all live births ranged from
periodontitis and low birth weight (adjusted odds ratio 1.55; 95% 5.5% (Finland) to 11.1% (Austria), for singleton births the range was
confidence interval: 1.04‑2.31). In the group with higher hemoglobin from 4.3% (Finland and Ireland) to 8.7% (Austria), and for multiple
A1c levels but still within the normal range ( between 5.6% and less births the range was from 42.2% (France) to 77.8% (Austria). During
than 6.5%), the findings showed no association between periodon- the follow-up period, singleton preterm birth rates decreased or
titis and low birth weight.30 Finally, Mahapatra et al,36 in a cross- remained stable in about half of the countries, such as in Estonia,
sectional study in India involving 156 women during weeks 13 to Finland, Germany, the Netherlands, Norway, Poland, Spain, and the
32 of gestation, found no association of probing pocket depth and United Kingdom (Scotland).
clinical attachment loss with low birth weight. However, bleeding on As part of a recent systematic review and meta-analysis on peri-
probing and gingival index were significantly higher in women with odontal diseases and adverse neonatal outcomes, region-based
low infant birth weight.36 subgroup risk analyses for preterm birth and low birth weight were
performed.40 Accordingly, African women with gingivitis or peri-
odontitis had a significantly higher risk for preterm birth (odds ratio
2.3 | Association with preterm birth and/or low 2.42; 95% confidence interval: 1.47‑4.00) in comparison with Asian
birth weight (odds ratio 1.31; 95% confidence interval: 1.04‑1.64) and European
women (odds ratio 1.52; 95% confidence interval: 1.27‑1.82).
From the four studies26–29 evaluating the association of periodon- Likewise, African women with gingivitis or periodontitis had signifi-
tal diseases with preterm low birth weight, only one, by Lafaurie cantly higher risk for low birth weight (odds ratio 14.74; 95% con-
et al, 29 showed a positive association with an adjusted odds ratio fidence interval: 5.30‑41.00) in comparison with Asian (odds ratio
|
10 BOBETSIS et al.
3.06; 95% confidence interval: 2.10‑4.47) and European women 15.27; 95% confidence interval: 1.18‑196.87) during pregnancy, but
(odds ratio 1.74; confidence interval:1.02‑2.97). not periodontitis, revealed an association with preterm birth.45 In
general, both Nordic and German study participants had homoge-
neous ethnic as well as socioeconomic backgrounds and enjoyed
4 | EU RO PE A N S T U D I E S O N good health care.45–48 Moreover, they expressed uniformly good
PE R I O D O NTA L D I S E A S E S A N D A DV E R S E periodontal health, which also might reflect the low prevalence
PR EG N A N C Y O U TCO M E S rates of periodontal pathogens in these study populations. For ex-
ample, the carriage rates of subgingival Porphyromonas gingivalis and
The European contribution on studies related to periodontal dis- Prevotella intermedia are seemingly rare among Finnish mothers.46,49
eases and adverse pregnancy outcomes is briefly summarized in Similarily, P. gingivalis and P. intermedia, as well as Aggregatibacter
Table 2. In general, the majority of data originate from case-control actinomycetemcomitans, Tannerella forsythia, and Fusobacterium nu-
or cohort studies, which have focused on the potential association cleatum, were not detectable or were observed only in low numbers
between periodontal diseases and preterm birth, whereas only a few among German women.48 Moreover, no periodontitis-associated
original publications on preterm premature rupture of membranes or factors increased the risk for preterm low birth weight (odds ratio
preeclampsia are available. 0.73; 95% confidence interval: 0.13‑4.19). On the contrary, in a
In a Czech cohort study, 78 women (median age of 31 years; Hungarian case-control study by Radnai et al, 50 the initial chronic
interquartile range 29‑36 years) with singleton pregnancies were localized periodontitis associated with preterm low birth weight (ad-
eligible for periodontal examination at the time of admission for justed odds ratio 3.32; 95% confidence interval: 1.64‑6.69) and the
preterm birth, and 77 age-matched women with uncomplicated prevalence and levels of all these five aforementioned periodontal
pregnancies served as controls.41 In comparison with controls, pathogens except P. intermedia were significantly higher (P < 0.001)
pregnant women with preterm premature rupture of membranes among mothers with periodontitis-associated preterm low birth
had higher (P < 0.0001) gingival and plaque indices as well as mean weight than among the control mothers.51
probing pocket depth and clinical attachment loss values before and Out of seven periodontal pathogens tested in subgingival samples
after adjustment for their smoking status. Similarly, in a Swiss proof Dutch women, Parvimonas micra was detected more frequently in
spective cohort study on 56 women (ie, 32 cases and 24 controls), the preeclampsia group (P = 0.040), whereas Campylobacter rectus
periodontal inflammation (defined by the periodontal screening was more prevalent among controls (P = 0.047).52 Moreover, after
index) was elevated during pregnancy and was more pronounced in adjustment for potential confounders (age, body mass index, smok-
women with preterm premature rupture of membranes (P < 0.05).42 ing, and socioeconomic status), a statistically significant association
In the large French Epipap case-control multicenter study on women was detected between periodontal diseases and preeclampsia (ad-
with preterm birth (n = 1108) and their controls without pregnancy justed odds ratio 7.9; 95% confidence interval: 1.9‑32.8).
complications (n = 1094), periodontitis was not associated with In conclusion, though there is evidence demonstrating an
spontaneous preterm birth or preterm premature rupture of mem- ethnicity-dependent association between periodontitis and preterm
branes.43 However, a significant association was detected between low birth weight/low birth weight, variations in the study population
maternal generalized periodontitis and induced preterm birth due sizes and methodologies are strong limitations in interpretation of
to preeclampsia (adjusted odds ratio 2.46; 95% confidence inter- the available data.
val: 1.58‑3.83). Noteworthy, in comparison with controls, is that
the cases more often had a nationality other than French (23.8% vs
18.2%; P = 0.002), as well as low educational level, unemployment 5 | I NTE RV E NTI O N S T U D I E S
during gestation, extreme pre-pregnancy body mass index values,
and smoked before and during gestation.43 In another multicenter Although the results from observational studies are not always
study with 230 cases and 520 controls run in Italy, no association consistent, there seems to be a consensus regarding the effect of
was detected between periodontal disease (as defined by having nonsurgical periodontal therapy during pregnancy on obstetric
mild or severe periodontitis) and any adverse pregnancy outcomes outcomes. Most of the systematic reviews that analyzed the high-
including preterm birth, low birth weight, preeclampsia, intrauterine quality randomized controlled trials reveal that nonsurgical peri-
growth restriction, and preterm premature rupture of membranes.44 odontal therapy during the second trimester of gestation is safe
There was no statistically significant difference between the cases and does not affect pregnancy outcomes.53–56 Using the terms of
and the controls with respect to country of birth, age, place of res- the recent clinical guidelines for the treatment of stages I-III peri-
idence, educational achievement, smoking, and periodontal status. odontitis,38 overall nonsurgical periodontal therapy in these studies
In contrast, no relation between preterm birth and periodontitis would include steps 1 and 2. However, a positive effect of periodon-
was demonstrated in previous Nordic studies, which include data tal treatment in women at high risk for adverse pregnancy outcomes
from Denmark,45 Finland,46 and Iceland.47 In the Danish study, es- needs to be further verified.57 Whether this lack of effect implies
tablished systemic risk factors, such as multiparity (odds ratio 16.7; that periodontal diseases do not contribute to adverse pregnancy
95% confidence interval: 1.77‑157.72) and smoking (odds ratio outcomes still remains to be elucidated, since logical concerns have
TA B L E 2 Overview of the European studies in relation to maternal periodontal disease and adverse pregnancy outcomes
Number of participants
Women with adverse Controls (women with Periodontal

BOBETSIS et al.
Country Reference Study type All pregnancy outcomes term gestation) examination Periodontal disease definition Outcomes Conclusion
Iceland Holbrook Cohort 96 6 90 In the beginning Probing pocket depth were Preterm birth No association between low-
et al47 of the 3rd assessed around the grade periodontitis and
trimester Ramfjord index teeth. preterm birth
Periodontitis: if ≥1 site with
Czech Radochova Cohort 155 78 77 At the median Full periodontal recordings Preterm birth, Pregnant women with
Republic et al41 Of those, 35 (44%) Of those, 22 (29%) gestational age from 4 sites per tooth. preterm preterm premature
had periodontitis had periodontitis of 33 wk +2 d Periodontitis: ≥2 sites with premature rupture of membranes
(the preterm clinical attachment loss rupture of interpreted increased
premature ≥3 mm and ≥2 sites with membranes plaque and bleeding
rupture of probing pocket depth ≥4 mm scores as well as higher
membranes (not on the same tooth), or probing pocket depth
group) and one site with ≥5 mm and clinical attachment
33 wk +1 d (the loss values in comparison
control group) with women with term
pregnancies (P < 0.0001)
Spain Aqueda Prospective 1296 85 (preterm birth), 78 1090 At 20 wk of Full mouth periodontal Preterm birth, A modest association
et al128 cohort (low birth weight), gestation recording. Periodontitis: ≥1 low birth between periodontitis
and 43 (preterm site with probing pocket weight, and preterm birth
low birth weight) depth ≥4 mm together with preterm low (adjusted odds ratio
clinical attachment loss birth weight 1.77; 95% confidence
≥3 mm on ≥4 teeth interval: 1.08‑2.88), but
no association between
periodontitis and low
birth weight or preterm
low birth weight
Spain Santa Cruz Prospective 170 a 5 (preterm birth), 6 157 Before 26 wk of Full mouth periodontal Preterm birth, Clinically no association
et al8 cohort (low birth weight), gestation recording. Generalized low birth between periodontal
and 2 (preterm moderate to severe weight, condition and preterm
low birth weight) periodontitis: ≥15 sites preterm low birth. However,
with clinical attachment birth weight the presence and
loss ≥3 mm (probing pocket counts of subgingival
depth >3 mm) Eikenella corrodens and
Capnocytohaga spp
associated with preterm
birth and low birth
weight, respectively
| 11
(Continues)
12
|

b
Spain Caneiro Prospective 158 Not available Not available During the 1st, Full mouth periodontal Preterm birth Periodontitis (stage II, grade
et al23 cohort 2nd, and 3rd recording. Periodontitis: B) did not associate with
trimesters interdental clinical preterm birth
attachment loss at ≥2
nonadjacent teeth,
or buccal/oral clinical
attachment loss ≥3 mm with
on ≥2 teeth
United Moore et al130 Prospective 3738 286 3452 Within 10‑14 wk of Full mouth periodontal Preterm birth No significant differences
Kingdom cohort gestation recording in plaque, probing
pocket depth, or clinical
attachment loss values
between the preterm
birth and control groups
United Farrell et al132 Prospective 1793 130 1663 Within 10‑14 wk of Full mouth periodontal Preterm birth, No association between
Kingdom cohort; all Includes a subgroup gestation recording low birth periodontitis and preterm
participants (n = 17) of weight, late birth or low birth weight.
never women with late miscarriage/ Potential association
smokers miscarriage/ stillbirth between high probing
stillbirth pocket depth values and
late miscarriage/stillbirth
Croatia Bosnjak Case-control 81 17 64 Within 2 d after Full periodontal recordings. Preterm birth Women with preterm birth
et al124 delivery Mean attachment level and had higher bleeding
its extent (extent N scores) on probing scores and
were determined deeper mean probing
pocket depth values.
Periodontitis associated
strongly with preterm
birth (adjusted odds ratio
8.13; 95% confidence
interval: 2.73‑45.9)
Denmark Skuldbøl Case-control 54 21 33 Within 11 mo Bleeding on probing and Preterm birth No relation between
et al45 postpartum probing pocket depth periodontitis and preterm
(cases) and 8 d recordings from 6 sites birth
postpartum of each tooth, and plaque
(controls) index from 3 index teeth
in each quadrant. Bone
level measurements were
performed from two
bitewing radiographs
BOBETSIS et al.

BOBETSIS et al.
Finland Heimonen Case-control 328 77 251 Within 2 d after Probing pocket depth from Preterm birth No differences in the oral
et al46 delivery 6 sites as well as visible health variables that
plaque index and bleeding could associate with
on probing recordings preterm birth
from 4 sites of all teeth.
Periodontitis: ≥1 site with
France Nabet et al43 Case-control 2212 1108 1094 2‑4 d after delivery Periodontal status was assessed Preterm birth Maternal periodontitis
multicenter Of those, 129 (11.6%) Of those, 118 (10.8%) at 6 sites per tooth on 14 associated with an
study had localized had localized teeth. Periodontitis: probing enhanced risk of induced
periodontitis periodontitis pocket depth ≥4 mm and preterm birth due to
and 148 (13.4%) and 118 (10.8%) clinical attachment loss preeclampsia and the
generalized generalized ≥3 mm on the same site association increased
periodontitis; periodontitis; either on 2 or 3 teeth with the extent of
263 (23.8%) had 199 (18.2%) had (localized periodontitis) or periodontitis (ie,
other than French other than French on ≥4 teeth (generalized generalized periodontitis):
nationality; nationality; periodontitis) • Any sites with probing
P = 0.002 P = 0.002 pocket depth ≥4 mm:
adjusted odds ratio 2.21;
1.48‑3.31
• Sites with probing pocket
depth ≥4 mm and bleeding
on probing: adjusted odds
ratio 1.94; 95% confidence
interval: 1.20‑3.13
• Sites with clinical
attachment loss ≥3 mm:
adjusted odds ratio 1.94;
1.31‑2.87
Germany Noack et al48 Case-control 101 59 42 Within 3 d after Full periodontal recordings. The Preterm low No association between
delivery severity of periodontitis birth weight periodontal status and
was defined based on preterm low birth weight
percentage of sites with
clinical attachment loss
≥3 mm
| 13
(Continues)
14
|

50
Hungary Radnai et al Case-control 161 77 84 Within 3 d after Full periodontal recordings, but Preterm low Initial chronic localized
Of those, 39 (50.7%) Of those, 18 (21.4%) delivery plaque index from Ramfjord birth weight periodontitis associated
had periodontitis had periodontitis teeth. Initial chronic with preterm low
(probing pocket (probing pocket localized periodontitis: ≥1 birth weight (adjusted
depth 4 mm depth 4 mm site with probing pocket odds ratio 3.32; 95%
and bleeding on and bleeding on depth ≥4 mm and bleeding confidence interval:
probing 50%); probing 50%); on probing ≥50% 1.64‑6.69), whereas
P = 0.0001 P = 0.0001 the most important
risk factor was smoking
1.20‑17.19)
Hungary Novák et al125 Case-control 242 77 165 Within 3 d after Probing pocket depth and Preterm birth, Poor periodontal status
delivery bleeding on probing from 6 low birth associated with preterm
sites of all teeth (except 3rd weight birth (adjusted odds ratio
molars). Poor periodontal 1.95; 95% confidence
status: ≥1 site with probing interval: 1.01‑3.74) and
pocket depth ≥4 mm and with low birth weight
bleeding on probing ≥50% (adjusted odds ratio 2.58;
1.29‑5.16)
Italy Giannella Case-control 820 400 420 Between 25 and Full-mouth periodontal Preterm birth Periodontitis associated with
et al126 Of those, 123 (30.8%) Of those, 52 (12.4%) 33 wk +6 d of recording. Periodontitis: preterm birth (adjusted
had periodontitis; had periodontitis; gestation probing pocket depth ≥4 mm odds ratio 2.83; 95%
P < 0.0001 P < 0.0001 and clinical attachment loss confidence interval:
≥3 mm on the same site on 1.86‑4.23)
≥4 teeth
Italy Abati et al44 Case-control 750 230 520 Within 5 d after Full-mouth periodontal Preterm birth, No association between
multicenter delivery recording. Periodontal low birth periodontitis and
study involvement categorized as weight, adverse pregnancy
follows. Healthy: all sites preeclampsia, outcomes, such as
with clinical attachment intrauterine preterm birth, low birth
loss <4 mm. Moderate: ≥1 growth weight, preeclampsia,
site with clinical attachment restriction, intrauterine growth
loss 4‑6 mm. Severe: ≥1 site preterm restriction, or preterm
with clinical attachment loss premature premature rupture of
≥6 mm rupture of membranes
membranes
BOBETSIS et al.
BOBETSIS et al.

127
Kosovo Meqa et al Case-control 200 40 160 Postpartum Full-mouth periodontal Preterm birth, Periodontitis associated with
recording. Periodontitis: ≥1 low birth preterm birth (odds ratio
site with probing pocket weight 3.4; 95% confidence
depth ≥5 mm and bleeding interval: 1.6‑7.3) and low
on probing, and ≥2 sites with birth weight (odds ratio
clinical attachment level to 3.2; 95% confidence
≥6 mm interval: 1.5‑6.8)
Netherlands Kunnen et al52 Case-control 52 17 35 Within 3‑28 mo Full-mouth periodontal Preeclampsia Periodontitis and its
Of those, 14 (82%) Of those, 13 (37%) after delivery recording. Mild severity associated with
had severe had severe periodontitis: 1‑15 sites with preeclampsia (adjusted
periodontitis; periodontitis; probing pocket depth ≥4 mm odds ratio 7.9; 95%
P = 0.009 P = 0.009 and bleeding on probing. confidence interval:
Severe periodontitis: ≥15 1.9‑32.8)
sites with probing pocket
depth ≥4 mm and bleeding
on probing
Romania Micu et al33 Case-control 194 74 120 Postpartum Full-mouth periodontal Preterm birth Periodontitis and its severity
recording. Periodontitis: ≥1 associated with preterm
site with probing pocket birth (adjusted odds ratio
depth ≥4 mm together with 3.46; 95% confidence
clinical attachment loss interval: 1.08‑11.15)
≥3 mm on ≥4 teeth
Switzerland Martinez de Prospective 429 84 345 Within 2‑3 d after Severe periodontitis: ≥2 Preterm birth Severe periodontitis
Tejada case-control Of those, 29 (34.5%) Of those, 61 (17.7%) delivery interproximal sites with associated with early
et al129 had severe had severe clinical attachment loss preterm birth (adjusted
periodontitis; periodontitis; ≥6 mm (not on the same odds ratio 2.38; 95%
P = 0.003 P = 0.003 tooth), and ≥1 interproximal confidence interval:
site with probing pocket 1.36‑4.14)
depth ≥5 mm
| 15
(Continues)
| 16

Switzerland Stadelmann Prospective 56 32 24 T1: 20‑34 wk of Periodontal screening index Preterm Periodontal inflammation
et al.42 case-control gestation; T2: was recorded based on premature was elevated during
within 2 d after periodontal probing at the rupture of pregnancy and more
delivery; T3: mesiobuccal and distobuccal membranes pronounced in women
4‑6 wk after sites of each tooth with preterm premature
delivery rupture of membranes
(P < 0.05). Between the
groups, however, no
significant differences
of periodontopathogen
prevalence in subgingival
and vaginal samples were
observed during the
follow-up
United Moore Case-control 154 61 93 Within 5 d after Full mouth periodontal Preterm birth No association between the
Kingdom et al.131 delivery recording severity of periodontal
disease and preterm birth
a
Based on the screening visit, participants were originally divided into two groups: the periodontitis group (n = 54) and the nonperiodontitis group (n = 116).
b
Based on the enrollment visit, 170 participants were originally divided into two groups: the periodontitis group (n = 42) and the nonperiodontitis group (n = 128). Owing to dropouts (n = 12) during the
follow-up, the final data analyses originated from 39 women with periodontitis and 119 women without periodontitis.
BOBETSIS et al.
|
BOBETSIS et al. 17
been raised, mainly regarding the appropriateness of the timing of 6.1 | Recent evidence from metastatic infection
intervention, the type of intervention, and the definition of success-
ful treatment.13 To date, several studies support that oral pathogens can reach and
During the last 5 years, only one quality randomized controlled invade the fetal-placental unit and induce pregnancy complications.
trial has been published. This relatively small study by Caneiro- The best line of evidence derives from three case reports where live
7
Queija et al included 40 patients with stage II grade B periodontitis. oral F. nucleatum or Bergeyella spp have been isolated from the am-
Subjects were randomly allocated to the control and test groups. The niotic fluid,75 the lung and stomach of an infant,76 and in the neo-
control group received only step 1 treatment (patient and profes- natal aspirates of complicated pregnancies.77 Moreover, numerous
sional supragingival dental biofilm control), whereas the test group studies have detected deoxyribonucleic acid from various peri-
also received step 2 treatment (subgingival instrumentation) before odontopathogens in different compartments of the fetal-placental
24 gestational weeks. Although a statistically significant reduction unit.78–82 In some cases these metastatic infections have also been
was verified in all clinical and microbiological parameters after peri- associated with various adverse pregnancy outcomes, as reviewed
odontal treatment in the test group, no significant differences were by Bobetsis et al.5
observed in the risk for preterm low birth weight. Over the past 5 years, several studies have also evaluated the
metastatic infection hypothesis in pregnant women. McCuaig
et al, 63 in a study conducted in Australia, investigated with mul-
6 | B I O LO G I C A L M EC H A N I S M S O F tiplex polymerase chain reaction (PCR) the presence of A. actino-
PE R I O D O NTA L D I S E A S E S A N D A DV E R S E mycetemcomitans, P. gingivalis and Fusobacterium spp in placental
PR EG N A N C Y O U TCO M E S tissues from 29 control women with uncomplicated term birth and
36 women with a spontaneous preterm labor and subsequent de-
Adverse pregnancy outcomes have been related to elevated local livery at less than 34 weeks of gestation. Their analysis showed
(intrauterine) and systemic inflammatory responses, as well as to significantly more Fusobacterium spp in the placentas from term
intrauterine infections. 58 On the other hand, periodontal diseases births than preterm birth (57.1% vs 13.3%, P = 0.01). In a study
are infectious inflammatory diseases of the gingiva and of the conducted in Switzerland, Mohr et al 64 evaluated 11 periodontal
supporting tissues of the teeth with potentially important sys- pathogens from 45 women with preterm premature rupture of
temic sequelae. Periodontal pathogens can enter the blood cir- membranes and 26 controls with uncomplicated pregnancies at
culation and induce a transient bacteremia. 59 At the same time, three time-p oints using multiplex PCR. The results showed no cor-
these pathogens and their by-p roducts, along with inflamma- relation between vaginal and gingival fluid microbiome. However,
tory mediators that are produced at the gingiva and spill into the different results were obtained in the study by Ye et al 67 held in
bloodstream, can initiate a chronic low-g rade systemic inflamma- Japan, who assessed with real-t ime PCR the presence of A. acti-
tory response. 60 nomycetemcomitans, P. gingivalis, T. forsythia, Treponema denticola,
Based on this fundamental knowledge, two major hypothet- F. nucleatum, and P. intermedia in the placentas of 28 women with
ical biological pathways, the direct and the indirect, have been threatened preterm labor and 36 healthy pregnant women. All six
proposed as the possible biological link between these “distant periodontopathic bacteria were detected in the placenta samples.
conditions.”10 In brief, in the direct pathway, via hematogenous The amount of F. nucleatum and the detection frequency of T. den-
dissemination, periodontal pathogens reach and invade the fetal- ticola were significantly higher in the threatened preterm labor
placental tissues, where they establish an ectopic site of infection group than in the healthy group. Ordinal logistic regression analy-
(metastatic infection). The presence of these pathogens and/or sis revealed that the presence of F. nucleatum in placental tissues
their by-products in the intrauterine compartment triggers a local was significantly associated with threatened preterm labor. Finally,
inflammatory response that will result in tissue damage (meta- in the study by Miranda-R ius et al 69 that took place in Tanzania the
static injury), leading to pregnancy complications. In the indirect authors used 16S ribosomal ribonucleic acid metagenomics tech-
pathway, inflammatory cytokines and mediators produced at the niques to evaluate the microbial profiles of placentas from women
gingival level in response to periodontal pathogens and/or acute- with or without periodontitis and with or without adverse preg-
phase reactants from the maternal liver induced by the systemic nancy outcomes. The results showed that the microbial load was
inflammatory response to periodontal infection accumulate at the low in all groups. The greatest differences were observed in the
intrauterine compartment. This induces an exacerbation of intra- group of mothers with periodontitis. Periodontitis had a notable
uterine inflammation (metastatic inflammation) that contributes to influence on the structure of the placental microbiota. Three phyla
pregnancy complications. and 44 genera were associated with periodontitis, whereas only
The evidence behind both these pathways has been extensively the Tenericutes phylum was associated with the adverse preg-
5,10–12
discussed in previous thorough and comprehensive reviews, nancy variable. Streptococcaceae and Mycoplasmataceae families
and recent mechanistic studies in humans and animal models are were associated with both periodontitis and adverse pregnancy
presented in Table 361–69 and Table 4,70–74 respectively. outcomes. Finally, although the differences for chorioamnionitis
18
TA B L E 3 Mechanistic studies in humans, since 2018, evaluating potential biological pathways that may explain the possible association between periodontal diseases and adverse pregnancy
|
outcomes
Study Sample size and groups Parameters evaluated Type of analyses Main findings
61
Ahmad et al 28 subjects with periodontal Clinical periodontal measurements, Plasma C-reactive protein levels in the test group were statistically
(Malaysia) disease (test group) and serum C-reactive protein significantly elevated compared with the control group
28 subjects with healthy (8.55 ± 5.28 mg/L vs 5.66 ± 2.91 mg/L). After nonsurgical
periodontium (control). The test periodontal therapy, a statistically significant reduction in the
group underwent nonsurgical C-reactive protein level in the test group (2.06 mg/L) along with
periodontal therapy, and the statistically significant improvement in periodontal status in both
control group was given oral groups was observed. The mean birth weight for infants of both
hygiene education groups showed no statistically significant difference
Latorre Uriza 23 women with high risk of preterm Clinical periodontal measurements, Cytometric bead array for Patients with periodontal disease showed higher levels of cytokines
et al62 birth and 23 women without serum interleukin-2, cytokines and enzyme- (interleukin-2, interleukin-6, interleukin-10, and tumor necrosis
(Colombia) high risk of preterm birth interleukin-4, interleukin-6, linked immunosorbent factor-alpha) and prostaglandin E2. Prostaglandin E2 increased
interleukin-10, tumor necrosis assay for prostaglandin E2 with the severity of periodontal disease. Patients at high risk for
factor-alpha, prostaglandin E2 preterm birth showed higher serum interleukin levels compared
with patients at low risk for preterm birth
McCuaig et al63 29 control women with Aggregatibacter Multiplex polymerase There were significantly more Fusobacterium spp in the placentas from
(Australia) uncomplicated term birth and actinomycetemcomitans, chain reaction was term births than preterm births (57.1% vs 13.3%, P, 0.01).
36 women with a spontaneous Porphyromonas gingivalis, and used for detection The multiplex polymerase chain reaction for Aggregatibacter
preterm labor and subsequent Fusobacterium spp in placental of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis resulted in
delivery at less than 34 wk tissues actinomycetemcomitans the generation of multiple nonspecific bands and, therefore, were
gestation and Porphyromonas not interpreted for analysis
gingivalis, and endpoint
polymerase chain reaction
was used for detection of
Fusobacterium spp
Mohr et al64 45 women with preterm premature Clinical periodontal measurements, Multiplex polymerase chain Though there was no correlation between vaginal and gingival fluid
(Switzerland) rupture of membranes and 26 subgingival, blood, vaginal, reaction and culture microbiome, cytokine levels in the assessed compartments
controls with uncomplicated and placenta sampling for differed between cases and controls. Vaginal smears did not show
pregnancies were examined at microbiologic, cytokine (C- a higher rate of abnormal flora in the cases at the onset of preterm
three time-points (T1: 20‑34 wk reactive protein, interleukin-1b, premature rupture of membranes. Number and variety of bacteria
of gestations; T2: within 48 h interleukin-6, interleukin-8, in the case group placental membranes and vagina were higher,
after delivery; T3: 4‑6 wk interleukin-10), and histology but these bacteria were not found in membranes at birth
postpartum). assessment
Yang et al65 Pilot study with 34 African Visual clinical periodontal No differences in overall microbiome diversity between the two
(USA) American women at 3rd evaluation; saliva interleukin-1b, groups, although significant differences were found among the
trimester of pregnancy (22 with matrix metalloproteinase-8, and bacterial taxa present. The gingivitis group had greater levels
healthy gingiva and 12 with C-reactive protein; subgingival of salivary interleukin-1beta and matrix metalloproteinase-8,
gingivitis) plaque samples for sequencing whereas C-reactive protein was not different between groups.
Overall microbiome diversity was positively associated with the
C-reactive protein level. No significant relationships among the
subgingival microbiome, periodontal inflammation, and preterm
birth
BOBETSIS et al.
Study Sample size and groups Parameters evaluated Type of analyses Main findings
Gómez et al.66 A total of 40 pregnant women Clinical periodontal evaluation, Multiplex flow cytometry All patients showed a predominant T helper 1 cytokine profile related
BOBETSIS et al.
(Colombia) divided into five groups and subgingival plaque assay to labor, characterized by interferon-gamma overexpression. The
according to placental infection sampling at the time of delivery. analysis by groups suggests that T helper 1 profile was trending to
and adverse pregnancy Placental interleukin-1beta, maintain cytotoxic cell activity by the expression of interleukin-15
outcome: (1) women without interleukin-6, interleukin-10, and granzyme B, except for the group with Porphyromonas
placental infection and interleukin-15, interleukin-17A, gingivalis–related placental infection and adverse pregnancy
without adverse pregnancy interleukin-17F, interleukin-21, outcome, which exhibited a reduction of interleukin-10 and
outcome (n = 17); (2) women interleukin-12p70, tumor interleukin-17F cytokines (P < 0.05)
with Porphyromonas gingivalis– necrosis factor-alpha, monocyte
related placental infection chemoattractant protein-1
and adverse pregnancy alpha, granzyme B, and
outcome (n = 5); (3) women interferon-gamma
with Porphyromonas gingivalis–
related placental infection and
without adverse pregnancy
outcome (n = 4); (4) women with
placental infection related to
urogenital microorganisms and
adverse pregnancy outcome
(n = 5); and (5) women without
placental infection with adverse
pregnancy outcome (n = 9)
Ye et al67 28 patients with threatened Aggregatibacter Real-time polymerase chain Thirteen of 64 births delivered preterm low birth weight infants. All 6
(Japan) preterm labor and 36 healthy actinomycetemcomitans, reaction and enzyme- periodontopathic bacteria were detected in the placenta samples.
pregnant women Porphyromonas gingivalis, linked immunosorbent The amount of Fusobacterium nucleatum and detection frequency
Tannerella forsythia, Treponema assay of Treponema denticola in placental samples were significantly
denticola, Fusobacterium higher in the threatened preterm labor group than in the healthy
nucleatum, and Prevotella group. Anti–Porphyromonas gingivalis immunoglobulin G in serum,
intermedia in subgingival plaque, amount of Porphyromonas gingivalis and Tannerella forsythia in
saliva, and placenta tissue. plaque samples, detection frequency of Prevotella intermedia
Serum immunoglobulin G titers in saliva, and percentage of pocket probing depth ≥5 mm were
against these bacteria higher in threatened preterm labor preterm low birth weight births
than in threatened preterm labor healthy delivery group and/
or in healthy delivery group. Ordinal logistic regression analysis
revealed that the presence of Fusobacterium nucleatum in placental
tissues was significantly associated with threatened preterm labor
| 19
(Continues)
|
20 BOBETSIS et al.
were not significant, this intra-amniotic infection was more fre-
associated with the adverse pregnancy variable. Streptococcaceae

Porphyromonas gingivalis in plaque might increase the risk of small
with periodontitis. The microbial load was low in all three groups.
placental microbiota. Three phyla and 44 genera were associated
intra-amniotic infection was more frequent in the placentas from

periodontitis and adverse pregnancy outcomes. Finally, although
quent in the placentas from mothers with periodontitis.
for gestational age and can be useful in prediction of small for

immunoglobulin G-4 are related with small for gestational age
the differences for chorioamnionitis were not significant, this

with periodontitis, whereas only the Tenericutes phylum was
The greatest differences were observed in the group of mothers
Periodontitis had a notable influence on the structure of the

in threatened preterm labor. Further, greater colonization of
higher anti–Porphyromonas gingivalis immunoglobulin G and
and Mycoplasmataceae families were associated with both

amounts are related to threatened preterm labor, whereas
Lower anti–Porphyromonas gingivalis immunoglobulin G-1
6.2 | Recent evidence from metastatic injury
The seeding of oral pathogens in the intrauterine compartments may
gestational age in threatened preterm labor

lead to an elevated local immune response that, in combination with
the induced tissue damage, may contribute to adverse pregnancy
outcomes. Valuable information regarding this metastatic injury de-
rives mainly from studies in animal models. Usually mono-infection
mothers with periodontitis

models in rodents have been used to mimic the complex multior-
ganism periodontal infection in pregnant women. The limitations are
obvious,5 but still these studies offer important indications of pos-
sible biological mechanisms associating periodontal diseases with
Main findings
adverse pregnancy outcomes.

Recently, only a few studies have evaluated aspects of meta-
static injury in animal models. Liang et al70 used a ligature infection
model in rats. P. gingivalis infection significantly increased maternal
serum levels of interferon-g amma and interleukin-1beta, whereas
polymerase chain reaction,
16S ribosomal ribonucleic

detection with real-time
Microbial composition with
no significant difference in the cytokine response was observed

immunosorbent assay
Porphyromonas gingivalis
with enzyme-linked
in the amniotic fluid. Rats with a preterm birth and newborns

acid metagenomics
immunoglobulin G
with low birth weight were observed in the P. gingivalis–infected

Type of analyses
group. Translocation of P. gingivalis to placentas was followed by

significantly enhanced expression of toll-like receptor-2 , as well
as Fas and Fas ligand. The elevated expression of toll-like recep-
tor-2 instead of toll-like receptor-4 should be anticipated, since, in
contrast to F. nucleatum and C. rectus, P. gingivalis signals through
toll-like receptor-2 . 83 Miyauchi et al71 used a different model
subclasses; small for gestational
gingivalis immunoglobulin G and
and subgingival plaque; serum
Porphyromonas gingivalis in saliva
where infection with P. gingivalis took place in the tooth pulp in

serum anti–Porphyromonas
Microbial profiles in placentas
mice. In P. gingivalis–infected placental tissue, the amniotic mem-

brane was degenerated, and necrosis was seen in the labyrinth and
Parameters evaluated
decidua. In addition, tumor necrosis factor-alpha, interleukin-8 ,

and cyclooxygenase-2 were upregulated in P. gingivalis–infected
placenta. Galectin-3 , an immune regulator, was significantly up-
regulated in placenta, amniotic fluid, and serum. Finally, Garcia-S o
age
et al73 used an intravenous infection model in mice and found

that F. nucleatum triggers placental inflammation and fetal death
through toll-like receptor-4–m ediated signaling, possibly from
pregnancy; group B: 12 women
with adverse pregnancy but no
periodontitis; and group C: 12
women with no periodontitis
Group A: 47 threatened preterm
endothelial cells of the placenta of maternal rather fetal origin.

labor patients; group B: 48
and no adverse pregnancy

periodontitis and adverse
healthy pregnant women
The placental inflammatory response followed a spatiotemporal

Group A: 12 women with
pattern. Interestingly, supplementation of pregnant mice with fish

Sample size and groups
oil as a source of omega-3 fatty acids suppressed placental inflam-

mation, reduced F. nucleatum proliferation in the placenta, and in-
creased fetal and neonatal survival.
6.3 | Recent evidence from metastatic

inflammation
Miranda-Rius
et al.69
(Tanzania)
Ye et al.68
Tracking inflammatory mediators produced at the gingival level and

(Japan)
Study
acute-phase reactants from the liver in the intrauterine compart-

ment would provide strong evidence of metastatic inflammation.
TA B L E 4 Mechanistic studies in animal models, since 2018, evaluating potential biological pathways that may explain the possible association between periodontal diseases and adverse
pregnancy outcomes
Reference Model of periodontitis Sample size and groups Parameters evaluated Main findings
70
BOBETSIS et al.
Liang et al Ligatures in rats 3 groups: (a) Porphyromonas Interferon-gamma, interleukin-1beta, and Porphyromonas gingivalis infection significantly increased the maternal
gingivalis–infected group interleukin-6 in serum and amniotic serum levels of interferon-gamma and interleukin-1beta, whereas
(periodontal ligature plus fluid, Porphyromonas gingivalis and no significant difference in the cytokine response was observed in
Porphyromonas gingivalis toll-like receptor-2 from placental the amniotic fluid. Rats with a preterm birth and low birth weight
infection); (b) negative specimens newborns were observed in the Porphyromonas gingivalis–infected
control group (ligature only, group. Translocation of Porphyromonas gingivalis to placentas
no Porphyromonas gingivalis was followed by significantly enhanced expression of toll-like
infection); and (c) blank receptor-2, as well as Fas and Fas ligand
control group (no ligature,
no Porphyromonas gingivalis
infection)
Miyauchi et al71 Porphyromonas 2 groups: (a) Porphyromonas Histology; gene expression of In Porphyromonas gingivalis–infected placental tissue the amniotic
gingivalis infection gingivalis–infected C57BL/6J cyclooxygenase-2, galectin-3, membrane was degenerated, and necrosis was seen in the
in the pulp of teeth mice; (b) control C57BL/6J mice interleukin-8/mKC, and tumor labyrinth and decidua. Tumor necrosis factor-alpha, interleukin-8,
in mice necrosis factor-alpha from placenta; and cyclooxygenase-2 were upregulated in Porphyromonas
galectin-3 concentrations in amniotic gingivalis–infected placenta. Galectin-3, an immune regulator, was
fluids and sera significantly upregulated in placenta, amniotic fluid, and serum
Fischer et al72 Mucosal colonization C57BL/6J and C57BL/6NCrl mice Fetal weight, Porphyromonas gingivalis Porphyromonas gingivalis infection induced low fetal weight in
model in mice colonization in placenta C57BL/6J but not in C57BL/6NCrl mice. Low fetal weight was
correlated with increasing amounts of Porphyromonas gingivalis
deoxyribonucleic acid in the placentas of the C57BL/6J dams. In
contrast, fetal weight in C57BL/6NCrl mice was independent of
Porphyromonas gingivalis in the placenta
Garcia-So et al73 Intravenous infection C57BL/6 wild-t ype Tie2-Cre, Vav1- Fusobacterium nucleatum colonization in Fusobacterium nucleatum triggers placental inflammation and fetal
of Fusobacterium iCre, Tlr4−/−Tlr4fl/fl mice various organs, inflammatory response death through toll-like receptor-4–mediated signaling. The
nucleatum in mice in the placenta evaluated by histology placental inflammatory response followed a spatiotemporal
and gene expression of inflammatory pattern. Supplementation of pregnant mice with fish oil as a
cytokines and chemokines source of omega-3 fatty acids suppressed placental inflammation,
reduced Fusobacterium nucleatum proliferation in the placenta, and
increased fetal and neonatal survival
Yoshida et al.74 Intravenous and oral 2 groups: (a) Porphyromonas Dam and fetal weight, gene expression in The body weight of Porphyromonas gingivalis dams was heavier
administration in gingivalis–infected C57BL/6J liver, and brown adipose tissue than that of control dams; however, the fetal body weight was
mice mice; (b) control C57BL/6J mice decreased in the offspring of Porphyromonas gingivalis dams.
Microarray analysis revealed 254 and 53 differentially expressed
genes in the liver and brown adipose tissue, respectively; mainly
downregulation of fatty acid metabolism gene set in the liver
and estrogen response early/late gene sets in the brown adipose
tissue, whereas inflammatory response and interleukin-6/Janus
kinase/signal transducer and activator of transcription 3 signaling
gene sets were upregulated both in the liver and brown adipose
tissue
| 21
|
22 BOBETSIS et al.
However, owing to the complex nature of these studies, most inves- 3. Guidelines for prevention of pregnancy complications or im-
tigations only assess the levels of these mediators in the serum and proved fertility in at-risk women before conception (dependent
try to relate them to adverse pregnancy outcomes. Therefore, the on identification of risk factors).
available evidence to support the indirect pathway is very weak, and 4. Guidelines for prevention of pregnancy complications or im-
the recent literature has not provided further insight on this path- proved fertility in all women before conception.
62
way. Specifically, in a study by Latorre Uriza et al held in Colombia,
pregnant women with periodontitis showed higher serum levels of
interleukin-2, interleukin-6, interleukin-10, tumor necrosis factor- 7.1 | Consideration of risk factors and study
alpha, and prostaglandin E2. Levels of prostaglandin E2 increased lifestyle challenges
with the severity of periodontitis. In addition, women at high risk for
preterm birth showed higher serum interleukin levels than women at Pregnancy outcome and fertility can be influenced by a wide range
low risk for preterm birth did. of risk factors.88–90 These may be potentially easily modified, modi-
fied with difficulty, or nonmodifiable. Therefore, we not only have to
consider the biological impact of each of these factors but also how
7 | G U I D E LI N E S A N D FU T U R E simple and straightforward modification of these is likely to be for
D I R EC TI O N S those at this time of life, where there are a large range of physiologic,
behavioral, economic, and sociological challenges at play.
It has been suggested that there is no justification for further epi- Current guidelines for management of periodontitis refer to be-
demiologic studies confirming associations between maternal peri- havioral modifications that are likely to have an indirect impact on
odontal diseases and pregnancy outcomes,5 and this would certainly some of these risk factors, include smoking cessation and control
appear to largely be the case. However, outstanding questions still of diabetes.38 Presently, weight loss and dietary counseling are not
exist, related to the exact nature of this relationship, which will im- part of these protocols, although, of course, this may change as more
pact not only on our understanding but also ultimately the inves- evidence emerges.
tigation, development, and delivery of potential therapies or care Even so, evidence suggests that dietary counseling and exercise
pathways that may then be of bilateral benefit. interventions can reduce the risk of gestational diabetes mellitus
The best way to approach this topic may be to consider the development; this may be limited in those who enter pregnancy al-
likely guidelines that are needed and then to understand what ready overweight or obese,91 suggesting that these changes may be
further investigations are needed to support these. These would most impactful before conception. Furthermore, periodontitis has
be dependent on a shared evidence base, based on studies as been proposed as a risk factor for gestational diabetes mellitus, al-
outlined in the following. Pragmatically, it may be necessary to though there are a number of shared risk factors.92,93 In addition,
also consider the cost-effectiveness of any oral interventions in there are robust data supporting the role for dietary and other life-
order to impact on health policy. However, given the increased style interventions in effective management of reduced fertility.94
prevalence of long-term morbidities associated with these com- Hence, holistic aspects of periodontal management may have other,
84
plications, simple periodontal care should prove acceptable. As less direct benefits.95
11
outlined by Figuero et al, it would appear important to focus on
the outcomes of preterm birth, low birth weight, and preeclamp-
sia. Beyond these, the issues of miscarriage/stillbirth and impaired 7.2 | Oral interventions/treatments are safe,
fertility may also be of importance, 85–87
but the support for any but are they always effective?
such association is less clear.
Recently, the European Federation of Periodontology launched Periodontal complications and exacerbations of existing inflamma-
the Oral Health & Pregnancy campaign (https://www.efp.org/ tory processes are a recognized event in pregnancy, and routine
for-patients/gum-disease-general-health/oral-health-pregnancy/), periodontal therapy in these scenarios is generally considered to be
which offers, in a simplified manner, advice and guidelines for both safe and effective for oral health improvement. A range of studies
health professionals and patients. However, the need for more de- have been carried out investigating the impact of periodontal ther-
tailed guidelines is obvious. Hence, potential guidelines for care apy during pregnancy on pregnancy outcome.6 Though these have
might be: employed a range of interventions and have not always reported
positive oral health outcomes and resolution of periodontitis,96,97
1. Guidelines for prevention of pregnancy complications in at-risk the consensus is that these forms of therapy have minimal impact on
women after pregnancy confirmation (dependent on identifi- pregnancy outcome.5
cation of risk factors). The failure of consistent success in oral health improvement may
2. Guidelines for prevention of pregnancy complications or im- be grounded in both biological and behavioral aspects. The consis-
proved fertility in all women after pregnancy confirmation. tent progressive upregulation of the gingival inflammatory response
|
BOBETSIS et al. 23
to dental biofilm alongside associated microbial changes98,99 is likely the endpoints of therapy have not been achieved with the previous
to impact on the threshold of dental biofilm levels for development steps—would be if it were delivered before conception, in order to
of clinically measurable change, 100,101 resulting in a higher risk of avoid microbiological local impacts from the very beginning of the
perceived treatment failure. More importantly, pregnancy is a diffi- pregnancy.
cult time for many mothers, who must balance many commitments
and challenges, and compliance with treatment and maintenance ap-
pointment schedules can be difficult.102–104 7.4 | Antibiotics/antimicrobials as part of an
This means that it may be necessary to reset targets for what intervention
may be considered a realistic target outcome in population studies.
However, before this is considered, it is first necessary to confirm Although routine oral interventions may have limited benefit, oral
that oral health improvement does have an impact. Hence, any ini- health outcomes may possibly be enhanced by the use of systemic
tial proof-of-concept studies will need to use all suitable means of antibiotics/antimicrobial drugs as part of step 2 therapy. Current
intensive step 1 and 2 therapy (including patient and professional guidelines38,108,109 do not advise use of these drugs in many peri-
supragingival dental biofilm control, subgingival instrumentation, odontal cases, but they may be of value in these specific situations
reevaluation) and regular and frequent professional maintenance under consideration here, should a new guideline be developed.
to establish and maintain improved oral health (and document this) Presently, it is unclear whether use of systemic antibiotics can posi-
throughout the pregnancy (perhaps in the style of Axelsson and tively impact fecundability in general, but this may be related to the
105
Lindhe ). Previous studies have used topical antimicrobials to max- quality of currently available data, and to the potentially wide range
imize oral treatment outcomes when investigating systemic links.106 of both indications and actions of these drugs.110 Hence, without
However, it is unclear whether it is appropriate for these agents to further studies, it is hard to establish whether a guideline change is
be employed during pregnancy; hence, they may not be a viable as- justified.
pect of any such future studies. This will require identification of and This is further complicated by data related to the impact of anti-
support for a group of motivated and concordant participants, and microbial drugs, especially when prescribed in the first and second
hence recruitment and retention may be challenging. Consequently, trimesters, suggesting increased risks of pregnancy complications;111
it may be necessary to overrecruit but also consider outcomes for an and although drugs such as metronidazole have been proposed to
incomplete treatment group alongside those successfully complet- prevent complications in the third trimester, the effectiveness of this
ing care and those in a matched control group who receive simple is debated.112,113 Clearly, if antimicrobials were to be used systemi-
care. cally, this may have to be limited to the preconception phase or later
in pregnancy,114 and the agents used chosen carefully.
7.3 | Timing of interventions

7.5 | Other mechanistic investigations related to
Historically, Bobetsis et al5 discussed the use of “more intense” in- risk and supporting basic science
terventions, including local mechanistic interventions such as sur-
gery or the use of systemic antimicrobials, in order to rapidly reduce Beyond the potential topics of interest outlined by Figuero et al,11
probing depths in a hopefully reliable manner. Using contemporane- the impact and severity of the host inflammatory response to he-
ous protocols, this would relate to the use of drugs for cases with matogenous spread of organisms may not be uniform between all
grade C disease or step 3 therapy, and the current consensus is that patients,115 in the same way as it may vary in periodontal dis-
this should only be considered after initial control of risk factors and eases.116,117 Consequently, there may be a shared proinflammatory
behavior modification. However, if we consider the evidence base phenotype seen in both tissues, such that an oral health intervention
around microbial hematogenous spread,107 and the ability for these may be less effective in women who may also be more susceptible
69
organisms to colonize remote organ sites, including the placenta, to periodontal inflammation at baseline (illustrated, perhaps, as more
then the use of mechanistic intraoral interventions of any sort during marginal inflammation) and who may also express a greater degree
pregnancy may, in fact, be closing the stable door after the horse has of chorioamnionitis. 24
bolted. This is clearly a problem if the patient presents after they dis- Consequently, a review of older data is justified if it is possible
cover that they are pregnant, since by then there has already been to relate oral inflammatory status at baseline to outcomes, as well as
a window of time for spread and colonization of organisms with as- for prospective in vivo studies to determine whether this also relates
sociated local inflammatory changes. Certainly, if patients wait until, to recognized single nucleotide polymorphisms such as interleukin-
for instance, they have developed pregnancy-associated gingivitis 1beta polymorphisms.118 Prospectively, there is a case for using
during a pregnancy, it is likely that oral interventions will be of lit- genome-wide association and whole-genome sequencing studies
tle obstetric benefit. The experimental data herein suggest that the to determine the presence and impact of genetic risk markers for,
only way that a conventional oral health intervention would be of and interactions between, maternal periodontal diseases and ad-
benefit, including steps 1 and 2—and possibly step 3 in cases where verse pregnancy outcomes.119 If present, these may then be used to
|
24 BOBETSIS et al.
further define women at risk of future complications, alongside rec- this field. This should integrate medical researchers working in this
ognized risk factors and previous medical history, allowing for other field to ensure that studies are designed to integrate well with other
confounders and their modulating impact on the host response. contemporaneous studies.
7.6 | What is the target population for studies? 8 | CO N C LU S I O N S
This leads to a need to consider studies on pregnancy outcomes for Studies from the last 5 years have not significantly altered our per-
at-risk women (based on medical history and previous pregnancy ception regarding the association between periodontal diseases and
history, perhaps supplemented by findings, as reported herein and adverse pregnancy outcomes. This will probably be the case with fu-
reported by workers such as Moutquin120) assessing preconception ture studies that do not take into consideration the methodological
improvements in oral health. This may be of benefit, but it does as- limitations that have been acknowledged and thoroughly discussed
sume that there are no other additional risk factors at play, such that by the scientific community. It also seems reasonable to suggest that
the majority of the risk for adverse outcome is related to oral health. new strategies and guidelines regarding intervention studies may be
If this is not the case then oral health improvements may still not be necessary in order to evaluate whether the establishment of peri-
enough to improve outcomes, and the use of this targeted popula- odontal health can improve pregnancy outcomes.
tion for a clinical trial may give a misleading answer without exten-
sive data collection. REFERENCES
It may be more productive to determine whether such an oral 1. Chawanpaiboon S, Vogel JP, Moller AB, et al. Global, regional,
health intervention would be of value for a much wider, well- and national estimates of levels of preterm birth in 2014: a sys-
tematic review and modelling analysis. Lancet Glob Health.
characterized but less “at-risk” population. However, given the low
2019;7(1):e37-e 46.
incidence of these problems, this necessitates large study popula- 2. Blencowe H, Krasevec J, de Onis M, et al. National, regional, and
tions. This work could be supplemented by interrogation of linked worldwide estimates of low birthweight in 2015, with trends from
national health care data sets (such as those described for studies 2000: a systematic analysis. Lancet Glob Health. 2019;7(7):e849
-e860.
investigating dementia in Taiwan121,122 and in South Korea123) to es-
3. Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional
tablish whether changes in systemic risk markers and/or oral health estimates of preeclampsia and eclampsia: a systematic review. Eur
interventions during pregnancy were related to alteration in obstet- J Obstet Gynecol Reprod Biol. 2013;170(1):1-7.
ric outcome. 4. Mathews TJ, Menacker F, MacDorman MF. Infant mortality statis-
tics from the 2001 period linked birth/infant death data set. Natl
Vital Stat Rep. 2003;52:1-28.
5. Bobetsis YA, Graziani F, Gursoy M, Madianos PN. Periodontal
7.7 | Research challenges disease and adverse pregnancy outcomes. Periodontol 2000.
2020;83(1):154-174.
The concept of periodontal impact on pregnancy outcome has been 6. Lopez NJ, Da Silva I, Ipinza J, Gutiérrez J. Periodontal ther-
apy reduces the rate of preterm low birth weight in women
investigated for approaching 30 years, and initial promising results
with pregnancy-associated gingivitis. J Periodontol. 2005;76(11
and apparently supportive basic scientific data led to the award of Suppl):2144-2153.
multiple large-scale grants in order to further identify the nature of 7. Caneiro-Q ueija L, Lopez-C arral J, Martin-L ancharro P, Limeres-
this relationship in clinical studies. Posse J, Diz-Dios P, Blanco-C arrion J. Non-surgical treatment of
periodontal disease in a pregnant Caucasian women population:
As already outlined, the outcomes of these projects, focused in
adverse pregnancy outcomes of a randomized clinical trial. Int J
care during pregnancy, were inconclusive. This may create further Environ Res Public Health. 2019;16(19):3638.
challenges in securing support for studies of the role, efficacy, and 8. Santa Cruz I, Herrera D, Martin C, Herrero A, Sanz M. Association
cost-effectiveness of preconception care, and a well-constructed between periodontal status and pre-term and/or low-birth weight
in Spain: clinical and microbiological parameters. J Periodontal Res.
argument with robust supporting data will be needed to enlighten
2013;48(4):443-451.
potential funders as to why further support is justified. Of course, it 9. Ide M, Papapanou PN. Epidemiology of association between ma-
will be challenging to secure funding for this kind of study, to recruit ternal periodontal disease and adverse pregnancy outcomes—
enough participants, and to be able to carry all associated basic sci- systematic review. J Clin Periodontol. 2013;40(Suppl 14):S181-S194.
10. Madianos PN, Bobetsis YA, Offenbacher S. Adverse pregnancy
ence investigations on one single cohort. Investigators may instead
outcomes (APOs) and periodontal disease: pathogenic mecha-
have to design and deliver several repeated studies, each investigat- nisms. J Clin Periodontol. 2013;40(Suppl 14):S170-S180.
ing different aspects of the relationships and proposed mechanisms, 11. Figuero E, Han YW, Furuichi Y. Periodontal diseases and ad-
to generate a mosaic understanding of the situation. There is a case verse pregnancy outcomes: mechanisms. Periodontol 2000.
2020;83(1):175-188.
to be made for development of an international consortium, to en-
12. Vander Haar EL, So J, Gyamfi-B annerman C, Han YW.
sure consistent methodologies and designs, avoid repetition where Fusobacterium nucleatum and adverse pregnancy outcomes:
unnecessary, and to allow cross-fertilization and interpretation of epidemiological and mechanistic evidence. Anaerobe. 2018;50:
results to deliver the best and most efficient outcomes for work in 55-59.
|
BOBETSIS et al. 25
13. Bobetsis YA, Madianos PN. Periodontitis and pregnancy and fer- 29. Lafaurie GI, Gomez LA, Montenegro DA, et al. Periodontal condi-
tility. In: Chapple I, ed. Periodontitis and Systemic Diseases: Clinical tion is associated with adverse perinatal outcomes and premature
Evidence and Biological Plausibility. Quintessence Publishing; rupture of membranes in low-income pregnant women in Bogota,
2021:183-218. Colombia: a case-control study. J Matern Fetal Neonatal Med.
14. Sanz M, Kornman K. Periodontitis and adverse pregnancy out- 2020;33(1):16-23.
comes: consensus report of the joint EFP/AAP workshop on peri- 30. Gomes-Filho IS, Trindade SC, da Cruz SS, et al. Mothers' high gly-
odontitis and systemic diseases. J Clin Periodontol. 2013;40(Suppl cemic levels and the association between periodontitis and low
14):S164-S169. birth weight. J Periodontol. 2022;93(7):954-965.
15. Petrini M, Gürsoy M, Gennai S, Graziani F. Biological mechanisms 31. Márquez-Corona ML, Tellez-Girón-Valdez A, Pontigo-Loyola AP,
between periodontal diseases and pregnancy complications. A et al. Preterm birth associated with periodontal and dental indi-
systematic review and meta-analysis of epidemiological associa- cators: a pilot case-control study in a developing country. J Matern
tion between adverse pregnancy outcomes and periodontitis: an Fetal Neonatal Med. 2021;34(5):690-695.
update of the review by Ide & Papapanou (2013). 2017 [Available 32. Uwambaye P, Munyanshongore C, Rulisa S, Shiau H, Nuhu A,
from: https://www.efp.org/fileadmin/uploads/efp/Documents/ Kerr MS. Assessing the association between periodontitis and
Campai gns/Oral_Health_and_Pregna ncy/Report s/review-biolo premature birth: a case-control study. BMC Pregnancy Childbirth.
gical-mechanisms-corr-4.0.pdf 2021;21(1):204.
16. Page RC, Eke PI. Case definitions for use in population- 33. Micu IC, Roman A, Ticala F, et al. Relationship between
based surveillance of periodontitis. J Periodontol. 2007;78(7 preterm birth and post-p artum periodontal maternal sta-
Suppl):1387-1399. tus: a hospital-b ased Romanian study. Arch Gynecol Obstet.
17. Tonetti MS, Claffey N. Advances in the progression of periodonti- 2020;301(5):1189-1198.
tis and proposal of definitions of a periodontitis case and disease 34. Gesase N, Miranda-Rius J, Brunet-Llobet L, Lahor-Soler E,
progression for use in risk factor research. Group C consensus Mahande MJ, Masenga G. The association between periodontal
report of the 5th European workshop in periodontology. J Clin disease and adverse pregnancy outcomes in northern Tanzania: a
Periodontol. 2005;32(Suppl 6):210-213. cross-sectional study. Afr Health Sci. 2018;18(3):601-611.
18. Manau C, Echeverria A, Agueda A, Guerrero A, Echeverria JJ. 35. Kopycka-Kedzierawski DT, Li D, Xiao J, Billings RJ, Dye TD.
Periodontal disease definition may determine the association be- Association of periodontal disease with depression and adverse
tween periodontitis and pregnancy outcomes. J Clin Periodontol. birth outcomes: results from the perinatal database; Finger Lakes
2008;35(5):385-397. region, New York state. PLoS One. 2019;14(4):e0215440.
19. Blanc AK, Wardlaw T. Monitoring low birth weight: an evaluation 36. Mahapatra A, Nayak R, Satpathy A, et al. Maternal periodon-
of international estimates and an updated estimation procedure. tal status, oral inflammatory load, and systemic inflamma-
Bull World Health Organ. 2005;83(3):178-185. tion are associated with low infant birth weight. J Periodontol.
20. Vivares-Builes AM, Rangel-Rincon LJ, Botero JE, Agudelo-Suarez 2021;92(8):1107-1116.
AA. Gaps in knowledge about the association between maternal 37. Tedesco RP, Galvao RB, Guida JP, et al. The role of maternal in-
periodontitis and adverse obstetric outcomes: an umbrella review. fection in preterm birth: evidence from the Brazilian multicentre
J Evid Based Dent Pract. 2018;18(1):1-27. study on preterm birth (EMIP). Clinics. 2020;75:e1508.
21. Daalderop LA, Wieland BV, Tomsin K, et al. Periodontal disease 38. Sanz M, Herrera D, Kebschull M, et al. Treatment of stage I-III
and pregnancy outcomes: overview of systematic reviews. JDR periodontitis—the EFP S3 level clinical practice guideline. J Clin
Clin Trans Res. 2018;3(1):10-27. Periodontol. 2020;47(Suppl 22):4-60.
22. Konopka T, Zakrzewska A. Periodontitis and risk for preeclamp- 39. Zeitlin J, Szamotulska K, Drewniak N, et al. Preterm birth time trends
sia—a systematic review. Ginekol Pol. 2020;91(3):158-164. in Europe: a study of 19 countries. BJOG. 2013;120(11):1356-1365.
23. Caneiro L, Lopez-C arral JM, Martin-L ancharro P, Linares A, 40. Zhang Y, Feng W, Li J, Cui L, Chen ZJ. Periodontal disease and ad-
Batalla P, Blanco-C arrion J. Periodontitis as a preterm birth risk verse neonatal outcomes: a systematic review and meta-analysis.
factor in Caucasian women: a cohort study. Oral Health Prev Dent. Front Pediatr. 2022;10:799740.
2020;18(1):77-8 4. 41. Radochova V, Stepan M, Kacerovska Musilova I, et al. Association
24. Erchick DJ, Khatry SK, Agrawal NK, et al. Risk of preterm birth between periodontal disease and preterm prelabour rupture of
associated with maternal gingival inflammation and oral hygiene membranes. J Clin Periodontol. 2019;46(2):189-196.
behaviours in rural Nepal: a community-based, prospective cohort 42. Stadelmann PF, Eick S, Salvi GE, et al. Increased periodontal in-
study. BMJ Open. 2020;10(8):e036515. flammation in women with preterm premature rupture of mem-
25. Lee YL, Hu HY, Chou SY, et al. Periodontal disease and preterm branes. Clin Oral Investig. 2015;19(6):1537-1546.
delivery: a nationwide population-based cohort study of Taiwan. 43. Nabet C, Lelong N, Colombier ML, et al. Maternal periodontitis
Sci Rep. 2022;12(1):3297. and the causes of preterm birth: the case-control Epipap study. J
26. Ye C, You M, Huang P, et al. Clinical study showing a lower Clin Periodontol. 2010;37(1):37-45.
abundance of Neisseria in the oral microbiome aligns with 44. Abati S, Villa A, Cetin I, et al. Lack of association between ma-
low birth weight pregnancy outcomes. Clin Oral Investig. ternal periodontal status and adverse pregnancy outcomes: a
2022;26(3):2465-2478. multicentric epidemiologic study. J Matern Fetal Neonatal Med.
27. Fogacci MF, de Cardoso EOC, da Barbirato DS, de Carvalho DP, 2013;26(4):369-372.
Sansone C. No association between periodontitis and preterm 45. Skuldbøl T, Johansen KH, Dahlén G, Stoltze K, Holmstrup P. Is pre-
low birth weight: a case-control study. Arch Gynecol Obstet. term labour associated with periodontitis in a Danish maternity
2018;297(1):71-76. ward? J Clin Periodontol. 2006;33(3):177-183.
28. Silveira da Mota Krüger M, Picanço Casarin RP, Dos Santos Pinto 46. Heimonen A, Rintamäki H, Furuholm J, Janket SJ, Kaaja R,
G, Pappen FG, Junqueira Camargo MB, Oliveira Bello Correa F, Meurman JH. Postpartum oral health parameters in women with
et al. Maternal periodontal disease and adverse perinatal out- preterm birth. Acta Odontol Scand. 2008;66(6):334-3 41.
comes: is there an association? A hospital-based case-control 47. Holbrook WP, Oskarsdottir A, Fridjonsson T, Einarsson H,
study. J Matern Fetal Neonatal Med 2019;32(20):3401–7. Hauksson A, Geirsson RT. No link between low-grade periodontal
|
26 BOBETSIS et al.
disease and preterm birth: a pilot study in a healthy Caucasian labor and preterm low birth weight cases: a longitudinal study
population. Acta Odontol Scand. 2004;62(3):177-179. in Japanese pregnant women. Clin Oral Investig. 2020;24(12):
48. Noack B, Klingenberg J, Weigelt J, Hoffmann T. Periodontal status 4261-4270.
and preterm low birth weight: a case control study. J Periodontal 68. Ye C, Kobayashi H, Katagiri S, et al. The relationship between the
Res. 2005;40(4):339-3 45. anti–Porphyromonas gingivalis immunoglobulin G subclass anti-
49. Gursoy M, Haraldsson G, Hyvonen M, Sorsa T, Pajukanta R, body and small for gestational age delivery: a longitudinal study in
Kononen E. Does the frequency of Prevotella intermedia increase pregnant Japanese women. Int Dent J. 2020;70(4):296-3 02.
during pregnancy? Oral Microbiol Immunol. 2009;24(4):299-3 03. 69. Miranda-Rius J, Brunet-Llobet L, Blanc V, et al. Microbial pro-
50. Radnai M, Gorzo I, Urban E, Eller J, Novak T, Pal A. Possible asso- file of placentas from Tanzanian mothers with adverse preg-
ciation between mother's periodontal status and preterm delivery. nancy outcomes and periodontitis. Oral Dis. 2023;29(2):772-785.
J Clin Periodontol. 2006;33(11):791-796. doi:10.1111/odi.13962
51. Urban E, Radnai M, Novak T, Gorzo I, Pal A, Nagy E. Distribution 70. Liang S, Ren H, Guo H, et al. Periodontal infection with
of anaerobic bacteria among pregnant periodontitis patients who Porphyromonas gingivalis induces preterm birth and lower birth
experience preterm delivery. Anaerobe. 2006;12(1):52-57. weight in rats. Mol Oral Microbiol. 2018;33(4):312-321.
52. Kunnen A, Blaauw J, van Doormaal JJ, et al. Women with a recent 71. Miyauchi M, Ao M, Furusho H, et al. Galectin-3 plays an important
history of early-onset pre-eclampsia have a worse periodontal role in preterm birth caused by dental infection of Porphyromonas
condition. J Clin Periodontol. 2007;34(3):202-207. gingivalis. Sci Rep. 2018;8(1):2867.
53. Polyzos NP, Polyzos IP, Zavos A, et al. Obstetric outcomes after 72. Fischer LA, Bittner-Eddy PD, Costalonga M. Fetal weight out-
treatment of periodontal disease during pregnancy: systematic re- comes in C57BL/6J and C57BL/6NCrl mice after oral colonization
view and meta-analysis. BMJ. 2010;341:c7017. with Porphyromonas gingivalis. Infect Immun. 2019;87(10):e00280
54. Uppal A, Uppal S, Pinto A, et al. The effectiveness of periodontal -e 00219.
disease treatment during pregnancy in reducing the risk of expe- 73. Garcia-So J, Zhang X, Yang X, et al. Omega-3 fatty acids suppress
riencing preterm birth and low birth weight: a meta-analysis. J Am Fusobacterium nucleatum-induced placental inflammation originat-
Dent Assoc. 2010;141(12):1423-1434. ing from maternal endothelial cells. JCI Insight. 2019;4(3):e125436.
55. Chambrone L, Pannuti CM, Guglielmetti MR, Chambrone LA. 74. Yoshida S, Hatasa M, Ohsugi Y, et al. Porphyromonas gingivalis ad-
Evidence grade associating periodontitis with preterm birth and/ ministration induces gestational obesity, alters gene expression in
or low birth weight: II. A systematic review of randomized trials the liver and brown adipose tissue in pregnant mice, and causes
evaluating the effects of periodontal treatment. J Clin Periodontol. underweight in fetuses. Front Cell Infect Microbiol. 2021;11:745117.
2011;38(10):902-914. 75. Han YW, Ikegami A, Bissada NF, Herbst M, Redline RW, Ashmead
56. Schwendicke F, Karimbux N, Allareddy V, Gluud C. Periodontal GG. Transmission of an uncultivated Bergeyella strain from the oral
treatment for preventing adverse pregnancy outcomes: a meta- cavity to amniotic fluid in a case of preterm birth. J Clin Microbiol.
and trial sequential analysis. PLoS One. 2015;10(6):e0129060. 2006;44(4):1475-1483.
57. Lopez NJ, Uribe S, Martinez B. Effect of periodontal treatment 76. Han YW, Fardini Y, Chen C, et al. Term stillbirth caused by
on preterm birth rate: a systematic review of meta-analyses. oral Fusobacterium nucleatum. Obstet Gynecol. 2010;115(2 Pt
Periodontol 2000. 2015;67(1):87-130. 2):442-4 45.
58. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection 77. Gonzales-Marin C, Spratt DA, Allaker RP. Maternal oral origin of
and preterm delivery. N Engl J Med. 2000;342(20):1500-1507. Fusobacterium nucleatum in adverse pregnancy outcomes as deter-
59. Forner L, Larsen T, Kilian M, Holmstrup P. Incidence of bacteremia mined using the 16S-23S rRNA gene intergenic transcribed spacer
after chewing, tooth brushing and scaling in individuals with peri- region. J Med Microbiol. 2013;62(Pt 1):133-144.
odontal inflammation. J Clin Periodontol. 2006;33(6):401-4 07. 78. Leon R, Silva N, Ovalle A, et al. Detection of Porphyromonas gingi-
60. Moutsopoulos NM, Madianos PN. Low-grade inflammation in valis in the amniotic fluid in pregnant women with a diagnosis of
chronic infectious diseases: paradigm of periodontal infections. threatened premature labor. J Periodontol. 2007;78(7):1249-1255.
Ann N Y Acad Sci. 2006;1088:251-264. 79. Mayatepek E, Zilow E, Pohl S. Severe intrauterine infection due to
61. Ahmad A, Nazar Z, Swaminathan D. C-reactive protein levels and Capnocytophaga ochracea. Biol Neonate. 1991;60(3–4):184-186.
periodontal diseases during pregnancy in Malaysian women. Oral 80. Gonzales-Marin C, Spratt DA, Millar MR, Simmonds M, Kempley
Health Prev Dent. 2018;16(3):281-289. ST, Allaker RP. Levels of periodontal pathogens in neonatal gastric
62. Latorre Uriza C, Velosa-Porras J, Roa NS, et al. Periodontal dis- aspirates and possible maternal sites of origin. Mol Oral Microbiol.
ease, inflammatory cytokines, and PGE2 in pregnant patients at 2011;26(5):277-290.
risk of preterm delivery: a pilot study. Infect Dis Obstet Gynecol. 81. Katz J, Chegini N, Shiverick KT, Lamont RJ. Localization of P. gingi-
2018;2018:7027683-7027687. valis in preterm delivery placenta. J Dent Res. 2009;88(6):575-578.
63. McCuaig R, Wong D, Gardiner FW, Rawlinson W, Dahlstrom JE, 82. Tateishi F, Hasegawa-Nakamura K, Nakamura T, et al. Detection of
Robson S. Periodontal pathogens in the placenta and membranes Fusobacterium nucleatum in chorionic tissues of high-risk pregnant
in term and preterm birth. Placenta. 2018;68:40-43. women. J Clin Periodontol. 2012;39(5):417-424.
64. Mohr S, Amylidi-Mohr SK, Stadelmann P, et al. Systemic inflamma- 83. Madianos PN, Bobetsis YA, Kinane DF. Generation of inflamma-
tion in pregnant women with periodontitis and preterm prelabor tory stimuli: how bacteria set up inflammatory responses in the
rupture of membranes: a prospective case-control study. Front gingiva. J Clin Periodontol. 2005;32(Suppl 6):57-71.
Immunol. 2019;10:2624. 84. Petrou S, Sach T, Davidson L. The long-term costs of preterm birth
65. Yang I, Knight AK, Dunlop AL, Corwin EJ. Characterizing the and low birth weight: results of a systematic review. Child Care
subgingival microbiome of pregnant African American women. J Health Dev. 2001;27(2):97-115.
Obstet Gynecol Neonatal Nurs. 2019;48(2):140-152. 85. Hart R, Doherty DA, Pennell CE, Newnham IA, Newnham JP.
66. Gómez LA, De Avila J, Castillo DM, et al. Porphyromonas gingivalis Periodontal disease: a potential modifiable risk factor limiting con-
placental atopobiosis and inflammatory responses in women with ception. Hum Reprod. 2012;27(5):1332-1342.
adverse pregnancy outcomes. Front Microbiol. 2020;11:591626. 86. Paju S, Oittinen J, Haapala H, Asikainen S, Paavonen J, Pussinen
67. Ye C, Katagiri S, Miyasaka N, et al. The periodontopathic bacteria PJ. Porphyromonas gingivalis may interfere with conception in
in placenta, saliva and subgingival plaque of threatened preterm women. J Oral Microbiol. 2017;9(1):1330644.
|
BOBETSIS et al. 27
87. Bond JC, Wise LA, Willis SK, et al. Self-reported periodontitis and 106. D'Aiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS. Short-term
fecundability in a population of pregnancy planners. Hum Reprod. effects of intensive periodontal therapy on serum inflammatory
2021;36(8):2298-2308. markers and cholesterol. J Dent Res. 2005;84(3):269-273.
88. Valero De Bernabe J, Soriano T, Albaladejo R, et al. Risk factors 107. Ye C, Kapila Y. Oral microbiome shifts during pregnancy and ad-
for low birth weight: a review. Eur J Obstet Gynecol Reprod Biol. verse pregnancy outcomes: hormonal and immunologic changes
2004;116(1):3-15. at play. Periodontol 2000. 2021;87(1):276-281.
89. Anderson K, Nisenblat V, Norman R. Lifestyle factors in people 108. Ide M. Periodontal diseases. In: Palmer NO, ed. Antimicrobial
seeking infertility treatment—a review. Aust N Z J Obstet Gynaecol. Prescribing in Dentistry: Good Practice Guidelines. 3rd ed. Faculty of
2010;50(1):8-20. General Dental Practice (UK) and Faculty of Dental Surgery; 2020.
90. Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors 109. Sgolastra F, Petrucci A, Ciarrocchi I, Masci C, Spadaro A. Adjunctive
and reproductive health: taking control of your fertility. Reprod systemic antimicrobials in the treatment of chronic periodontitis:
Biol Endocrinol. 2013;11:66. a systematic review and network meta-analysis. J Periodontal Res.
91. Bennett CJ, Walker RE, Blumfield ML, et al. Interventions de- 2021;56(2):236-248.
signed to reduce excessive gestational weight gain can reduce the 110. Crowe HM, Wesselink AK, Wise LA, et al. Antibiotics and fecund-
incidence of gestational diabetes mellitus: a systematic review and ability among female pregnancy planners: a prospective cohort
meta-analysis of randomised controlled trials. Diabetes Res Clin study. Hum Reprod. 2021;36(10):2761-2768.
Pract. 2018;141:69-79. 111. Omranipoor A, Kashanian M, Dehghani M, Sadeghi M, Baradaran
92. Xiong X, Elkind-Hirsch KE, Vastardis S, Delarosa RL, Pridjian HR. Association of antibiotics therapy during pregnancy with
G, Buekens P. Periodontal disease is associated with gesta- spontaneous miscarriage: a systematic review and meta-analysis.
tional diabetes mellitus: a case-control study. J Periodontol. Arch Gynecol Obstet. 2020;302(1):5-22.
2009;80(11):1742-1749. 112. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent
93. Chokwiriyachit A, Dasanayake AP, Suwannarong W, et al. preterm delivery in pregnant women with asymptomatic bacterial
Periodontitis and gestational diabetes mellitus in non-smoking fe- vaginosis. N Engl J Med. 2000;342(8):534-540.
males. J Periodontol. 2013;84(7):857-862. 113. Klebanoff MA, Carey JC, Hauth JC, et al. Failure of metronida-
94. Panth N, Gavarkovs A, Tamez M, Mattei J. The influence of diet zole to prevent preterm delivery among pregnant women with
on fertility and the implications for public health nutrition in the asymptomatic Trichomonas vaginalis infection. N Engl J Med.
United States. Front Public Health. 2018;6:211. 2001;345(7):487-493.
95. Silvestris E, Lovero D, Palmirotta R. Nutrition and female fertility: 114. Nguyen MH, Fornes R, Kamau N, et al. Antibiotic use during preg-
an interdependent correlation. Front Endocrinol. 2019;10:346. nancy and the risk of preterm birth: a population-based Swedish
96. Michalowicz BS, Hodges JS, DiAngelis AJ, et al. Treatment of cohort study. J Antimicrob Chemother. 2022;77(5):1461-1467.
periodontal disease and the risk of preterm birth. N Engl J Med. 115. Couceiro J, Matos I, Mendes JJ, Baptista PV, Fernandes AR,
2006;355(18):1885-1894. Quintas A. Inflammatory factors, genetic variants, and predispo-
97. Newnham JP, Newnham IA, Ball CM, et al. Treatment of periodon- sition for preterm birth. Clin Genet. 2021;100(4):357-367.
tal disease during pregnancy: a randomized controlled trial. Obstet 116. Brodzikowska A, Gorski B. Polymorphisms in genes involved in
Gynecol. 2009;114(6):1239-1248. inflammation and periodontitis: a narrative review. Biomolecules.
98. Carrillo-de-Albornoz A, Figuero E, Herrera D, Bascones-Martinez 2022;12(4):552. doi:10.3390/biom12040552
A. Gingival changes during pregnancy: II. Influence of hor- 117. Shaddox LM, Morford LA, Nibali L. Periodontal health and disease:
monal variations on the subgingival biofilm. J Clin Periodontol. the contribution of genetics. Periodontol 2000. 2021;85(1):161-181.
2010;37(3):230-240. 118. Moore S, Ide M, Randhawa M, Walker JJ, Reid JG, Simpson NA.
99. Carrillo-d e-A lbornoz A, Figuero E, Herrera D, Cuesta P, An investigation into the association among preterm birth, cy-
Bascones-M artinez A. Gingival changes during pregnancy: III. tokine gene polymorphisms and periodontal disease. BJOG.
Impact of clinical, microbiological, immunological and socio- 2004;111(2):125-132.
demographic factors on gingival inflammation. J Clin Periodontol. 119. Strauss JF 3rd, Romero R, Gomez-Lopez N, et al. Spontaneous
2012;39(3):272-283. preterm birth: advances toward the discovery of genetic predispo-
100. Figuero E, Carrillo-de-Albornoz A, Herrera D, Bascones-Martinez sition. Am J Obstet Gynecol. 2018;218(3):294-314.e2.
A. Gingival changes during pregnancy: I. Influence of hormonal 120. Moutquin JM. Socio-economic and psychosocial factors in
variations on clinical and immunological parameters. J Clin the management and prevention of preterm labour. BJOG.
Periodontol. 2010;37(3):220-229. 2003;110(Suppl 20):56-60.
101. Figuero E, Carrillo-de-Albornoz A, Martin C, Tobias A, Herrera 121. Lee YL, Hu HY, Huang LY, Chou P, Chu D. Periodontal disease asso-
D. Effect of pregnancy on gingival inflammation in systemi- ciated with higher risk of dementia: population-based cohort study
cally healthy women: a systematic review. J Clin Periodontol. in Taiwan. J Am Geriatr Soc. 2017;65(9):1975-1980.
2013;40(5):457-473. 122. Ma KS, Hasturk H, Carreras I, et al. Dementia and the risk of
102. Quinn GP, Detman LA, Bell-Ellison BA. Missed appointments in periodontitis: a population-based cohort study. J Dent Res.
perinatal care: response variations in quantitative versus qualita- 2022;101(3):270-277.
tive instruments. J Med Pract Manage. 2008;23(5):307-313. 123. Kim DH, Jeong SN, Lee JH. Severe periodontitis with tooth loss as
103. Heaman MI, Sword W, Elliott L, et al. Barriers and facilitators re- a modifiable risk factor for the development of Alzheimer, vascular,
lated to use of prenatal care by inner-city women: perceptions of and mixed dementia: National Health Insurance Service-National
health care providers. BMC Pregnancy Childbirth. 2015;15:2. Health Screening Retrospective Cohort 2002-2015. J Periodontal
104. Heaman MI, Sword W, Elliott L, et al. Perceptions of barriers, facil- Implant Sci. 2020;50(5):303-312.
itators and motivators related to use of prenatal care: a qualitative 124. Bosnjak A, Relja T, Vucićević-Boras V, Plasaj H, Plancak D. Pre-
descriptive study of inner-city women in Winnipeg, Canada. SAGE term delivery and periodontal disease: a case-control study from
Open Med. 2015;3:2050312115621314. Croatia. J Clin Periodontol. 2006;33:710-716.
105. Axelsson P, Lindhe J. Effect of controlled oral hygiene procedures 125. Novák T, Németh G, Kozinszky Z, Urbán E, Gorzó I, Radnai M.
on caries and periodontal disease in adults. J Clin Periodontol. Could poor periodontal status be a warning sign for worse preg-
1978;5(2):133-151. nancy outcome? Oral Health Prev Dent. 2020;18:165-170.
|
28 BOBETSIS et al.
126. Giannella L, Giulini S, Cerami LB, LaMarca A, Forabosco A, 131. Moore S, Randhawa M, Ide M. A case-control study to investigate
Volpe A. Periodontal disease and nitric oxide levels in low risk an association between adverse pregnancy outcome and peri-
women with preterm labor. Eur J Obstet Gynecol Reprod Biol. odontal disease. J Clin Periodontol. 2005;32(1):1-5.
2011;158:47-51. 132. Farrell S, Ide M, Wilson RF. The relationship between maternal
127. Meqa K, Dragidella F, Disha M, Sllamniku-Dalipi Z. The associa- periodontitis, adverse pregnancy outcome and miscarriage in
tion between periodontal disease and preterm low birthweight in never smokers. J Clin Periodontol. 2006;33(2):115-120.
Kosovo. Acta Stomatol Croat. 2017;51:33-4 0.
128. Agueda A, Ramon JM, Manau C, Guerrero A, Echeverria JJ.
Periodontal disease as a risk factor for adverse pregnancy
outcomes: a prospective cohort study. J Clin Periodontol.
2008;35:16-22.
How to cite this article: Bobetsis YA, Ide M, Gürsoy M,
129. Martinez de Tejada B, Gayet-A geron A, Combescure C, Irion O,
Baehni P. Association between early preterm birth and periodonti- Madianos PN. Periodontal diseases and adverse pregnancy
tis according to USA and European consensus definitions. J Matern outcomes. Present and future. Periodontol 2000. 2023;00:1-
Fetal Neonatal Med. 2012;25:2160-2166. 28. doi:10.1111/prd.12486
130. Moore S, Ide M, Coward PY, et al. A prospective study to inves-
tigate the relationship between periodontal disease and adverse
pregnancy outcome. Br Dent J. 2004;197(5):251-258.

Periodontology 2000 - 2023 - Bobetsis - Periodontal Diseases and Adverse Pregnancy Outcomes Present and Future

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Periodontology 2000 - 2023 - Bobetsis - Periodontal Diseases and Adverse Pregnancy Outcomes Present and Future

Uploaded by

Copyright:

Available Formats

Received: 11 October 2022 | Revised: 2 February 2023 | Accepted: 11 March 2023

Periodontal diseases and adverse pregnancy outcomes. Present

Yiorgos A. Bobetsis1 | Mark Ide2 | Mervi Gürsoy3 | Phoebus N. Madianos1

1 | I NTRO D U C TI O N several methodologic limitations remain a significant drawback for

Periodontology 2000. 2023;00:1–28. ﻿ wileyonlinelibrary.com/journal/prd | 1

Women with adverse Controls (women with Periodontal

Women with adverse Controls (women with Periodontal

Women with adverse Controls (women with Periodontal

Women with adverse Controls (women with Periodontal

Women with adverse Controls (women with Periodontal

Women with adverse Controls (women with Periodontal

were not significant, this intra-­amniotic infection was more fre-

associated with the adverse pregnancy variable. Streptococcaceae

placental microbiota. Three phyla and 44 genera were associated

intra-­amniotic infection was more frequent in the placentas from

for gestational age and can be useful in prediction of small for

the differences for chorioamnionitis were not significant, this

Periodontitis had a notable influence on the structure of the

and Mycoplasmataceae families were associated with both

6.2 | Recent evidence from metastatic injury

The seeding of oral pathogens in the intrauterine compartments may

gestational age in threatened preterm labor

mothers with periodontitis

adverse pregnancy outcomes.

16S ribosomal ribonucleic

Microbial composition with

no significant difference in the cytokine response was observed

in the amniotic fluid. Rats with a preterm birth and newborns

with low birth weight were observed in the P. gingivalis–­infected

group. Translocation of P. gingivalis to placentas was followed by

where infection with P. gingivalis took place in the tooth pulp in

Microbial profiles in placentas

mice. In P. gingivalis–­infected placental tissue, the amniotic mem-

decidua. In addition, tumor necrosis factor-­alpha, interleukin-­8 ,

et al73 used an intravenous infection model in mice and found

endothelial cells of the placenta of maternal rather fetal origin.

and no adverse pregnancy

The placental inflammatory response followed a spatiotemporal

pattern. Interestingly, supplementation of pregnant mice with fish

oil as a source of omega-­3 fatty acids suppressed placental inflam-

6.3 | Recent evidence from metastatic

Tracking inflammatory mediators produced at the gingival level and

acute-­phase reactants from the liver in the intrauterine compart-

7.3 | Timing of interventions

7.6 | What is the target population for studies? 8 | CO N C LU S I O N S

You might also like

Periodontology 2000. 2023;00:1–28. wileyonlinelibrary.com/journal/prd | 1

were not significant, this intra-amniotic infection was more fre-

intra-amniotic infection was more frequent in the placentas from

with low birth weight were observed in the P. gingivalis–infected

mice. In P. gingivalis–infected placental tissue, the amniotic mem-

decidua. In addition, tumor necrosis factor-alpha, interleukin-8 ,

oil as a source of omega-3 fatty acids suppressed placental inflam-

acute-phase reactants from the liver in the intrauterine compart-